1-oxyalkyl-2-carboxy-7-nonsubstituted indole derivatives

ABSTRACT

Compounds of Formula I 
                         
wherein A 1 , B 1 , C 1 , D 1 , E 1 , F 1  and L 1  are as defined herein, which inhibit the activity of anti-apoptotic Mcl-1 protein, compositions containing the compounds, and methods of treating diseases involving overexpressed or unregulated Mdl-1 protein, such as leukemia and lymphoma, are disclosed.

CROSS-REFERENCE SECTION TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/104,319, filed Apr. 16, 2008 now U.S. Pat. No. 7,981,888, whichclaims the benefit of U.S. Provisional Patent Application No.60/949,683, filed Jul. 13, 2007, and U.S. Provisional Patent ApplicationNo. 60/912,049, filed Apr. 16, 2007, each of which is herebyincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity ofanti-apoptotic Mcl-1 protein, compositions containing the compounds, andmethods of treating diseases involving overexpressed or unregulatedMcl-1 protein.

BACKGROUND OF THE INVENTION

Mcl-1 protein is associated with a number of diseases. There istherefore an existing need in the therapeutic arts for compounds whichbind to and inhibit the activity of Mcl-1 protein.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds whichinhibit the activity of Mcl-1 protein, the compounds having Formula I,

and therapeutically acceptable salts thereof, wherein

L¹ is a bond or is alkylene, alkenylene or alkynylene;

A¹ is C(O)OH, or a bioisostere thereof, or is C(O)OR¹, C(O)OR², C(O)OR³or C(O)OR⁴;

one, two, three, four or each of B¹, C¹, D¹, E¹ and F¹ are independentlyR¹, R², R³ or R⁴, OR¹, SR¹, S(O)R¹, SO₂R¹, NH₂, NHR¹, N(R¹)₂, C(O)R¹,C(O)NH₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHSO₂R¹, NR¹SO₂R¹,NHC(O)OR¹, NR¹C(O)OR¹, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHC(O)NH₂,NHC(O)R¹NHC(O)N(R¹)₂, NR¹C(O)N(R¹)₂, OR², SR², S(O)R², SO₂R², NH₂, NHR²,N(R²)₂, C(O)R², C(O)NH₂, C(O)NHR², C(O)N(R²)₂, NHC(O)R², NR²C(O)R²,NHSO₂R², NR²SO₂R², NHC(O)OR², NR²C(O)OR², SO₂NH₂, SO₂NHR², SO₂N(R²)₂,NHC(O)NH₂, NHC(O)R²NHC(O)N(R²)₂, NR¹C(O)N(R²)₂, OR³, SR³, S(O)R³, SO₂R³,NH₂, NHR³, N(R³)₂, C(O)R³, C(O)NH₂, C(O)NHR³, C(O)N(R³)₂, NHC(O)R³,NR²C(O)R³, NHSO₂R³, NR³SO₂R³, NHC(O)OR³, NR³C(O)OR³, SO₂NH₂, SO₂NHR³,SO₂N(R³)₂, NHC(O)NH₂, NHC(O)R³NHC(O)N(R³)₂, NR¹C(O)N(R³)₂, OR⁴, SR⁴,S(O)R⁴, SO₂R⁴, NH₂, NHR⁴, N(R⁴)₂, C(O)R⁴, C(O)NH₂, C(O)NHR⁴, C(O)N(R⁴)₂,NHC(O)R⁴, NR⁴C(O)R⁴, NHSO₂R⁴, NR⁴SO₂R⁴, NHC(O)OR⁴, NR⁴C(O)OR⁴, SO₂NH₂,SO₂NHR⁴, SO₂N(R⁴)₂, NHC(O)NH₂, NHC(O)R⁴, NHC(O)N(R⁴)₂ or NR¹C(O)N(R⁴)₂,and the remainder are H, OH, CN, F, Cl, Br or I;

R¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(1A); R^(1A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R² is heteroaryl which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(3A);R^(3A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, NH₂, NHR⁵, N(R⁵)₂, C(O)R⁵, C(O)NH₂,C(O)NHR⁵, C(O)N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHSO₂R⁵, NR⁵SO₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, NHC(O)NH₂, NHC(O)R⁵,NHC(O)N(R⁵)₂, NR⁵C(O)N(R⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F,Cl, Br or I;

R⁵ is R⁶, R⁷, R⁸ or R⁹,

R⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(6A); R^(6A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(7A); R^(7A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(8A);R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR^(9A), OR^(9A), SR^(9A), S(O)R^(9A), SO₂R^(9A), NH₂, NHR^(9A),N(R^(9A))₂, C(O)R^(9A), C(O)NH₂, C(O)NHR^(9A), C(O)N(R^(9A))₂,NHC(O)R^(9A), NR^(9A)C(O)R^(9A), NHSO₂R^(9A), NR^(9A)SO₂R^(9A),NHC(O)OR^(9A), NR^(9A)C(O)OR^(9A), SO₂NH₂, SO₂NHR^(9A), SO₂N(R^(9A))₂,NHC(O)NH₂, NHC(O)R^(9A)NHC(O)N(R^(9A))₂, NR^(9A)C(O)N(R^(9A))₂, OH, (O),C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I;

R^(9A) is R^(9B), R^(9C) or R^(9D);

R^(9B) is phenyl which is unfused or fused with benzene, heteroarene orR^(9B2); R^(9B2) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R^(9C) is heteroaryl which is unfused or fused with benzene, heteroareneor R^(9C2); R^(9C2) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R^(9D) is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(9D2); R^(9D2) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein each foregoing cyclic moiety is independently unsubstituted orsubstituted with one or two or three or four or five of independentlyselected R¹⁰, OR¹⁰, OCH₂R¹⁰, SR¹⁰, S(O)R¹⁰, SO₂R¹⁰, C(O)R¹⁰, CO(O)R¹⁰,OC(O)R¹⁰, OC(O)OR¹⁰, NO₂, NH₂, NHR¹⁰, N(R¹⁰)₂, CH₂R¹⁰, C(O)NH₂,C(O)NHR¹⁰, C(O)N(R¹⁰)₂, NHC(O)R¹⁰, NR¹⁰C(O)R¹⁰, C(O)NHOH, C(O)NHOR¹⁰,C(O)NHSO₂R¹⁰, C(O)NR¹⁰SO₂R¹⁰, SO₂NH₂, SO₂NHR¹⁰, SO₂N(R¹⁰)₂, CF₃, CF₂CF₃,C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹⁰, C(N)N(R¹⁰)₂, ═NO-(alkylene)-C(O)CF₃,CNOH, CNOCH₃, OH, (O), N₃, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R¹⁰ is R¹¹, R¹², R¹³ or R¹⁴;

R¹¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(11A); R^(11A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹² is heteroaryl which is unfused or fused with benzene, heteroarene orR^(12A); R^(12A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(13A);R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, C(O)R¹⁵, C(O)NH₂,C(O)NHR¹⁵, C(O)N(R¹⁵)₂, NHC(O)R¹⁵, NR¹⁵C(O)R¹⁵, NHSO₂R¹⁵, NR¹⁵SO₂R¹⁵,NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, NHC(O)NH₂,NHC(O)R¹⁵NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NR¹⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃,CF₂CF₃, F, Cl, Br or I;

R¹⁵ is R¹⁶, R¹⁷, R¹⁸ or R¹⁹;

R¹⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(15A); R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁷ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(16A); R^(16A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(18A);R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with R²⁰;

R²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;

wherein R¹¹, R¹², R¹³, R¹⁶, R¹⁷, and R¹⁸ are independently unsubstitutedor substituted with one or two or three or four or five of independentlyR²¹, OR²¹, OCH₂R²¹, SR²¹, S(O)R²¹, SO₂R²¹, C(O)R²¹, CO(O)R²¹, OC(O)R²¹,OC(O)OR²¹, NO₂, NH₂, NHR²¹, N(R²¹)₂, CH₂R²¹, C(O)NH₂, C(O)NHR²¹,C(O)N(R²¹)₂, NHC(O)R²¹, NR²¹C(O)R²¹, C(O)NHOH, C(O)NHOR²¹, C(O)NHSO₂R²¹,C(O)NR²¹SO₂R²¹, SO₂NH₂, SO₂NHR²¹, SO₂N(R²¹)₂, CF₃, CF₂CF₃, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR²¹, C(N)N(R²¹)₂, ═NO-(alkylene)-C(O)CF₃, CNOH,CNOCH₃, OH, (O), N₃, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I; and

R²¹ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl or heterocycloalkyl.

Still another embodiment pertains to compounds having Formula I,

and therapeutically acceptable salts thereof, wherein

L¹ is a bond or is alkylene, alkenylene or alkynylene;

A¹ is C(O)OH, or a bioisostere thereof, or is C(O)OR¹, C(O)OR², C(O)OR³or C(O)OR⁴;

one, two, three, four or each of B¹, C¹, D¹, E¹ and F¹ are independentlyR¹, R², R³ or R⁴, OR¹, SR¹, S(O)R¹, SO₂R¹, NH₂, NHR¹, N(R¹)₂, C(O)R¹,C(O)NH₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHSO₂R¹, NR¹SO₂R¹,NHC(O)OR¹, NR¹C(O)OR¹, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHC(O)NH₂,NHC(O)R¹NHC(O)N(R¹)₂, NR¹C(O)N(R¹)₂, OR², SR², S(O)R², SO₂R², NH₂, NHR²,N(R²)₂, C(O)R², C(O)NH₂, C(O)NHR², C(O)N(R²)₂, NHC(O)R², NR²C(O)R²,NHSO₂R², NR²SO₂R², NHC(O)OR², NR²C(O)OR², SO₂NH₂, SO₂NHR², SO₂N(R²)₂,NHC(O)NH₂, NHC(O)R²NHC(O)N(R²)₂, NR¹C(O)N(R²)₂, OR³, SR³, S(O)R³, SO₂R³,NH₂, NHR³, N(R³)₂, C(O)R³, C(O)NH₂, C(O)NHR³, C(O)N(R³)₂, NHC(O)R³,NR²C(O)R³, NHSO₂R³, NR³SO₂R³, NHC(O)OR³, NR³C(O)OR³, SO₂NH₂, SO₂NHR³,SO₂N(R³)₂, NHC(O)NH₂, NHC(O)R³NHC(O)N(R³)₂, NR¹C(O)N(R³)₂, OR⁴, SR⁴,S(O)R⁴, SO₂R⁴, NH₂, NHR⁴, N(R⁴)₂, C(O)R⁴, C(O)NH₂, C(O)NHR⁴, C(O)N(R⁴)₂,NHC(O)R⁴, NR⁴C(O)R⁴, NHSO₂R⁴, NR⁴SO₂R⁴, NHC(O)OR⁴, NR⁴C(O)OR⁴, SO₂NH₂,SO₂NHR⁴, SO₂N(R⁴)₂, NHC(O)NH₂, NHC(O)R⁴, NHC(O)N(R⁴)₂ or NR¹C(O)N(R⁴)₂,and the remainder are H, OH, CN, F, Cl, Br or I;

R¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(1A); R^(1A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R² is heteroaryl which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(3A);R^(3A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, NH₂, NHR⁵, N(R⁵)₂, C(O)R⁵, C(O)NH₂,C(O)NHR⁵, C(O)N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHSO₂R⁵, NR⁵SO₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, NHC(O)NH₂, NHC(O)R⁵,NHC(O)N(R⁵)₂, NR⁵C(O)N(R⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F,Cl, Br or I;

R⁵ is R⁶, R⁷, R⁸ or R⁹,

R⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(6A); R^(6A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷ is unfused or fused with benzene, heteroarene or R^(7A); R^(7A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(8A);R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR^(9A), OR^(9A), SR^(9A), S(O)R^(9A), SO₂R^(9A), NH₂, NHR^(9A),N(R^(9A))₂, C(O)R^(9A), C(O)NH₂, C(O)NHR^(9A), C(O)N(R^(9A))₂,NHC(O)R^(9A), NR^(9A)C(O)R^(9A), NHSO₂R^(9A), NR^(9A)SO₂R^(9A),NHC(O)OR^(9A), NR^(9A)C(O)OR^(9A), SO₂NH₂, SO₂NHR^(9A), SO₂N(R^(9A))₂,NHC(O)NH₂, NHC(O)R^(9A)NHC(O)N(R^(9A))₂, NR^(9A)C(O)N(R^(9A))₂, OH, (O),C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I;

R^(9A) is R^(9B), R^(9C) or R^(9D);

R^(9B) is phenyl which is unfused or fused with benzene, heteroarene orR^(9B2); R^(9B2) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R^(9C) is heteroaryl which is unfused or fused with benzene, heteroareneor R^(9C2); R^(9C2) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R^(9D) is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(9D2); R^(9D2) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein each foregoing cyclic moiety is independently unsubstituted orsubstituted with one or two or three or four or five of independentlyselected R¹⁰, OR¹⁰, OCH₂R¹⁰, SR¹⁰, S(O)R¹⁰, SO₂R¹⁰, C(O)R¹⁰, CO(O)R¹⁰,OC(O)R¹⁰, OC(O)OR¹⁰, NO₂, NH₂, NHR¹⁰, N(R¹⁰)₂, CH₂R¹⁰, C(O)NH₂,C(O)NHR¹⁰, C(O)N(R¹⁰)₂, NHC(O)R¹⁰, NR¹⁰C(O)R¹⁰, C(O)NHOH, C(O)NHOR¹⁰,C(O)NHSO₂R¹⁰, C(O)NR¹⁰SO₂R¹⁰, SO₂NH₂, SO₂NHR¹⁰, SO₂N(R¹⁰)₂, CF₃, CF₂CF₃,C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹⁰, C(N)N(R¹⁰)₂, ═NO-(alkylene)-C(O)CF₃,CNOH, CNOCH₃, OH, (O), N₃, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R¹⁰ is R¹¹, R¹², R¹³ or R¹⁴;

R¹¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(11A); R^(11A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹² is heteroaryl which is unfused or fused with benzene, heteroarene orR^(12A); R^(12A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(13A);R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, C(O)R¹⁵, C(O)NH₂,C(O)NHR¹⁵, C(O)N(R¹⁵)₂, NHC(O)R¹⁵), NR¹⁵C(O)R¹⁵, NHSO₂R¹⁵, NR¹⁵SO₂R¹⁵,NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, NHC(O)NH₂,NHC(O)R¹⁵NHC(O)N(R¹⁵)₂, NR¹⁵C(O)N(R¹⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃,CF₂CF₃, F, Cl, Br or I;

R¹⁵ is R¹⁶, R¹⁷, R¹⁸ or R¹⁹;

R¹⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(15A); R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁷ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(16A); R^(16A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(18A);R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with R²⁰;

R²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;

wherein R¹¹, R¹², R¹³, R¹⁶, R¹⁷, and R¹⁸ are independently unsubstitutedor substituted with one or two or three or four or five of independentlyR²¹, OR²¹, OCH₂R²¹, SR²¹, S(O)R²¹, SO₂R²¹, C(O)R²¹, CO(O)R²¹, OC(O)R²¹,OC(O)OR²¹, NO₂, NH₂, NHR²¹, N(R²¹)₂, CH₂R²¹, C(O)NH₂, C(O)NHR²¹,C(O)N(R²¹)₂, NHC(O)R²¹, NR²¹C(O)R²¹, C(O)NHOH, C(O)NHOR²¹, C(O)NHSO₂R²¹,C(O)NR²¹SO₂R²¹, SO₂NH₂, SO₂NHR²¹, SO₂N(R²¹)₂, CF₃, CF₂CF₃, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR²¹, C(N)N(R²¹)₂, ═NO-(alkylene)-C(O)CF₃, CNOH,CNOCH₃, OH, (O), N₃, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I; and

R²¹ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl or heterocycloalkyl.

with or without administering one or more than one additionaltherapeutic agents and with or without also administering radiotherapythereto.

Still another embodiment pertains to compounds having Formula I,

and therapeutically acceptable salts thereof, wherein

L¹ is a bond or is alkylene, alkenylene or alkynylene;

A¹ is C(O)OH, or a bioisostere thereof, or is C(O)OR¹, C(O)OR², C(O)OR³or C(O)OR⁴;

one, two, three, four or each of B¹, C¹, D¹, E¹ and F¹ are independentlyR¹, R², R³ or R⁴, OR¹, SR¹, S(O)R¹, SO₂R¹, NH₂, NHR¹, N(R¹)₂, C(O)R¹,C(O)NH₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHSO₂R¹, NR¹SO₂R¹,NHC(O)OR¹, NR¹C(O)OR¹, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHC(O)NH₂,NHC(O)R¹NHC(O)N(R¹)₂, NR¹C(O)N(R¹)₂, OR², SR², S(O)R², SO₂R², NH₂, NHR²,N(R²)₂, C(O)R², C(O)NH₂, C(O)NHR², C(O)N(R²)₂, NHC(O)R², NR²C(O)R²,NHSO₂R², NR²SO₂R², NHC(O)OR², NR²C(O)OR², SO₂NH₂, SO₂NHR², SO₂N(R²)₂,NHC(O)NH₂, NHC(O)R²NHC(O)N(R²)₂, NR¹C(O)N(R²)₂, OR³, SR³, S(O)R³, SO₂R³,NH₂, NHR³, N(R³)₂, C(O)R³, C(O)NH₂, C(O)NHR³, C(O)N(R³)₂, NHC(O)R³,NR²C(O)R³, NHSO₂R³, NR³SO₂R³, NHC(O)OR³, NR³C(O)OR³, SO₂NH₂, SO₂NHR³,SO₂N(R³)₂, NHC(O)NH₂, NHC(O)R³NHC(O)N(R³)₂, NR¹C(O)N(R³)₂, OR⁴, SR⁴,S(O)R⁴, SO₂R⁴, NH₂, NHR⁴, N(R⁴)₂, C(O)R⁴, C(O)NH₂, C(O)NHR⁴, C(O)N(R⁴)₂,NHC(O)R⁴, NR⁴C(O)R⁴, NHSO₂R⁴, NR⁴SO₂R⁴, NHC(O)OR⁴, NR⁴C(O)OR⁴, SO₂NH₂,SO₂NHR⁴, SO₂N(R⁴)₂, NHC(O)NH₂, NHC(O)R⁴, NHC(O)N(R⁴)₂ or NR¹C(O)N(R⁴)₂,and the remainder are H, OH, CN, F, Cl, Br or I;

R¹ phenyl which is unfused or fused with benzene, heteroarene or R^(1A);R^(1A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R² heteroaryl which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(3A);R^(3A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, NH₂, NHR⁵, N(R⁵)₂, C(O)R⁵, C(O)NH₂,C(O)NHR⁵, C(O)N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHSO₂R⁵, NR⁵SO₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, NHC(O)NH₂, NHC(O)R⁵,NHC(O)N(R⁵)₂, NR⁵C(O)N(R⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F,Cl, Br or I;

R⁵ is R⁶, R⁷, R⁸ or R⁹,

R⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(6A); R^(6A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(7A); R^(7A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(8A);R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR^(9A), OR^(9A), SR^(9A), S(O)R^(9A), SO₂R^(9A), NH₂, NHR^(9A),N(R^(9A))₂, C(O)R^(9A), C(O)NH₂, C(O)NHR^(9A), C(O)NHR^(9A),C(O)N(R^(9A))₂, NHC(O)R^(9A), NR^(9A)C(O)R^(9A), NHSO₂R^(9A),NR^(9A)SO₂R^(9A), NHC(O)OR^(9A), NR^(9A)C(O)OR^(9A), SO₂NH₂,SO₂NHR^(9A), SO₂N(R^(9A))₂, NHC(O)NH₂, NHC(O)R^(9A) NHC(O)N(R^(9A))₂,NR^(9A)C(O)N(R^(9A))₂, OH, (O), C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Bror I;

R^(9A) is R^(9B), R^(9C) or R^(9D);

R^(9B) is phenyl which is unfused or fused with benzene, heteroarene orR^(9B2); R^(9B2) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R^(9C) is heteroaryl which is unfused or fused with benzene, heteroareneor R^(9C2); R^(9C2) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R^(9D) is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(9D2); R^(9D2) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein each foregoing cyclic moiety is independently unsubstituted orsubstituted with one or two or three independently selected R¹⁰, OR¹⁰,C(O)R¹⁰, NO₂, N(R¹⁰)₂, C(O)NHR¹⁰, SO₂N(R¹⁰)₂, C(O)OH, OH, (O), CF₃,OCF₃, F, Cl, Br or I;

R¹⁰ is R¹¹, R¹², R¹³ or R¹⁴;

R¹¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(11A); R^(11A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹² is heteroaryl which is unfused or fused with benzene, heteroarene orR^(12A); R^(12A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(13A);R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, C(O)R¹⁵, C(O)NH₂,C(O)NHR¹⁵, C(O)N(R¹⁵)₂, NHC(O)R¹⁵, NR¹⁵C(O)R¹⁵, NHSO₂R¹⁵, NR¹⁵SO₂R¹⁵,NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, NHC(O)NH₂,NHC(O)R¹⁵NHC(O)N(R¹⁵)₂, NR¹⁵C(O)N(R¹⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃,CF₂CF₃, F, Cl, Br or I;

R¹⁵ is R¹⁶, R¹⁷, R¹⁸ or R¹⁹;

R¹⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(15A); R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁷ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(16A); R^(16A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(18A);R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with R²⁰;

R²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;

wherein R¹¹, R¹², R¹³, R¹⁶, R¹⁷, and R¹⁸ are independently unsubstitutedor substituted with one or two or three or four or five of independentlyOR²¹, NO₂, CF₃, F, Cl, Br or I; and

R²¹ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl or heterocycloalkyl.

Still another embodiment pertains to compounds having Formula I,

and therapeutically acceptable salts thereof, wherein

L¹ is a bond or is alkylene, alkenylene or alkynylene;

A¹ is C(O)OH, or a bioisostere thereof, or is C(O)OR¹, C(O)OR², C(O)OR³or C(O)OR⁴;

one, two, three, four or each of B¹, C¹, D¹, E¹ and F¹ are independentlyR¹, R², R³ or R⁴, OR¹, SR¹, S(O)R¹, SO₂R¹, NH₂, NHR¹, N(R¹)₂, C(O)R¹,C(O)NH₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, OR², SR², S(O)R², SO₂R², NH₂, NHR²,N(R²)₂, C(O)R², C(O)NH₂, SO₂NH₂, SO₂NHR², SO₂N(R²)₂, NHC(O)NH₂, OR³,SR³, S(O)R³, SO₂R³, NH₂, NHR³, N(R³)₂, C(O)R³, C(O)NH₂, SO₂NH₂, SO₂NHR³,SO₂N(R³)₂, OR⁴, SR⁴, S(O)R⁴, SO₂R⁴, NH₂, NHR⁴, N(R⁴)₂, C(O)R⁴, C(O)NH₂,SO₂NH₂, SO₂NHR⁴ or SO₂N(R⁴)₂, and the remainder are H, OH, CN, F, Cl, Bror I;

R¹ is phenyl which is unfused or fused with benzene;

R² is heteroaryl;

R³ is cycloalkyl, cycloalkenyl or heterocycloalkyl;

R⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, NH₂, NHR⁵, N(R⁵)₂, C(O)R⁵, C(O)NH₂,C(O)NHR⁵, C(O)N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHSO₂R⁵, NR⁵SO₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, NHC(O)NH₂, NHC(O)R⁵,NHC(O)N(R⁵)₂, NR⁵C(O)N(R⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F,Cl, Br or I;

R⁵ is R⁶, R⁷, R⁸ or R⁹,

R⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(6A); R^(6A) is cycloalkane;

R⁷ is heteroaryl;

R⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

R⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR^(9A), OR^(9A), SR^(9A), S(O)R^(9A), SO₂R^(9A), NH₂, NHR^(9A),N(R^(9A))₂, C(O)R^(9A), C(O)NH₂, C(O)NHR^(9A), C(O)N(R^(9A))₂,NHC(O)R^(9A), NR^(9A)C(O)R^(9A), NHSO₂R^(9A), NR^(9A)SO₂R^(9A),NHC(O)OR^(9A), NR^(9A)C(O)OR^(9A), SO₂NH₂, SO₂NHR^(9A), SO₂N(R^(9A))₂,NHC(O)NH₂, NHC(O)R^(9A)NHC(O)N(R^(9A))₂, NR^(9A)C(O)N(R^(9A))₂, OH, (O),C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br or I;

R^(9A) is R^(9B), R^(9C) or R^(9D);

R^(9B) is phenyl;

R^(9C) is heteroaryl;

R^(9D) is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl;

wherein each foregoing cyclic moiety is independently unsubstituted orsubstituted with one or two or three independently selected R¹⁰, OR¹⁰,C(O)R¹⁰, NO₂, N(R¹⁰)₂, C(O)NHR¹⁰, SO₂N(R¹⁰)₂, C(O)OH, OH, (O), CF₃,OCF₃, F, Cl, Br or I;

R¹⁰ is R¹¹, R¹², R¹³ or R¹⁴;

R¹¹ is phenyl which is unfused or fused with benzene;

R¹² is heteroaryl;

R¹³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

R¹⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, C(O)R¹⁵, C(O)NH₂,C(O)NHR¹⁵, C(O)N(R¹⁵)₂, NHC(O)R¹⁵, NR¹⁵C(O)R¹⁵, NHSO₂R¹⁵, NR¹⁵SO₂R¹⁵,NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, NHC(O)NH₂,NHC(O)R¹⁵NHC(O)N(R¹⁵)₂, NR¹⁵C(O)N(R¹⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃,CF₂CF₃, F, Cl, Br or I;

R¹⁵ is R¹⁶, R¹⁷, R¹⁸ or R¹⁹;

R¹⁶ is phenyl;

R¹⁷ is heteroaryl;

R¹⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

R¹⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with R²⁰;

R²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;

wherein R¹¹, R¹², R¹³, R¹⁶, R¹⁷, and R¹⁸ are independently unsubstitutedor substituted with one or two or three or four or five of independentlyOR²¹, NO₂, CF₃, F, Cl, Br or I; and

R²¹ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl or heterocycloalkyl.

Still another embodiment pertains to compounds having Formula I,

and therapeutically acceptable salts thereof, wherein

L¹ is a bond;

A¹ is C(O)OH;

one, two, three, four or each of B¹, C¹, D¹, E¹ and F¹ are independentlyR¹, R², R³ or R⁴, NHR¹OR⁴, and the remainder are H, OH, CN, F, Cl, Br orI;

R¹ is phenyl which is unfused or fused with benzene;

R² is heteroaryl;

R³ is cycloalkyl, cycloalkenyl or heterocycloalkyl;

R⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR⁵, OR⁵, SR⁵, NH₂, NHR⁵, N(R⁵)₂, C(O)R⁵, NHC(O)R⁵, F, Cl, Br or I;

R⁵ is R⁶, R⁷, R⁸ or R⁹,

R⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(6A); R^(6A) is cycloalkane;

R⁷ is heteroaryl;

R⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

R⁹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one, two, three, four or five of independently selectedR^(9A), F, Cl, Br or I;

R^(9A) is R^(9B), R^(9C) or R^(9D);

R^(9B) is phenyl;

R^(9C) is heteroaryl;

R^(9D) is cycloalkyl;

wherein each foregoing cyclic moiety is independently unsubstituted orsubstituted with one or two or three independently selected R¹⁰, OR¹⁰,C(O)R¹⁰, NO₂, N(R¹⁰)₂, C(O)NHR¹⁰, SO₂N(R¹⁰)₂, C(O)OH, OH, (O), CF₃,OCF₃, F, Cl, Br or I;

R¹⁰ is R¹¹, R¹³ or R¹⁴;

R¹¹ is phenyl which is unfused or fused with benzene;

R¹³ is heterocycloalkyl;

R¹⁴ is alkyl or alkenyl, each of which is unsubstituted or substitutedwith one, two, three, four or five of independently selected R¹⁵, OR¹⁵,SO₂R¹⁵, N(R¹⁵)₂, F, Cl, Br or I;

R¹⁵ is R¹⁶, R¹⁸ or R¹⁹;

R¹⁶ is phenyl;

R¹⁸ is heterocycloalkyl;

R¹⁹ is alkyl;

wherein R¹¹ and R¹⁶ are independently unsubstituted or substituted withone or two or three or four or five of independently OR²¹, NO₂, CF₃, F,Cl, Br or I; and

R²¹ is alkyl.

Still another embodiment pertains to

-   3-(3-cyclohexylpropyl)-1H-indole-2-carboxylic acid;-   3-(4-cyclohexylbutyl)-1H-indole-2-carboxylic acid;-   3-(3-(3-chlorophenoxy)propyl)-1H-indole-2-carboxylic acid;-   3-(3-(3-(trifluoromethyl)phenoxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;-   3-(3-(2-benzylphenoxy)propyl)-1H-indole-2-carboxylic acid;-   3-(3-(2,3-dihydro-1H-inden-5-yloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-((3-methyl-1-naphthyl)oxy)propyl)-1H-indole-2-carboxylic acid;-   3-(3-((2-methyl-1-naphthyl)oxy)propyl)-1H-indole-2-carboxylic acid;-   3-(3-(1-naphthylthio)propyl)-1H-indole-2-carboxylic acid;-   5-bromo-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;-   3-(3-(1-naphthyloxy)propyl)-5-((1E)-3-phenylprop-1-enyl)-1H-indole-2-carboxylic    acid;-   5-((E)-2-cyclohexylvinyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthyloxy)propyl)-5-((E)-2-phenylvinyl)-1H-indole-2-carboxylic    acid;-   5-(4-fluorophenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthyloxy)propyl)-5-(2-phenylethyl)-1H-indole-2-carboxylic    acid;-   3-(3-((7-methyl-2,3-dihydro-1H-inden-4-yl)oxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(4-fluorophenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthyloxy)propyl)-6-((E)-2-phenylvinyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthyloxy)propyl)-6-((1E)-3-phenylprop-1-enyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthyloxy)propyl)-4-((1E)-3-phenylprop-1-enyl)-1H-indole-2-carboxylic    acid;-   6-(3-(benzyloxy)phenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(3-(benzyloxy)phenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-bromo-3-(4-(1-naphthyloxy)butyl)-1H-indole-2-carboxylic acid;-   1-methyl-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;-   3-(3-(1-naphthyloxy)propyl)-6-phenyl-1H-indole-2-carboxylic acid;-   6-(2-methylphenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   6-(3-methylphenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   6-(4-methylphenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(1-naphthyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(((3-(dimethylamino)propyl)amino)carbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(1,1′-biphenyl-2-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-methylphenyl)-1-(3-(2-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-methylphenyl)-1-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-chlorophenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-phenyl-1H-indole-2-carboxylic acid;-   1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxylicacid;-   3-(2,3-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2,5-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3,4-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3,5-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2,5-dimethoxyphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3,4-dimethoxyphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-methylphenyl)-1-(4-(1-naphthyloxy)butyl)-1H-indole-2-carboxylic    acid;-   3-(2-methylphenyl)-1-(4-(2-naphthyloxy)butyl)-1H-indole-2-carboxylic    acid;-   1-(4-(2,3-dichlorophenoxy)butyl)-3-(2-methylphenyl)-1H-indole-2-carboxylic    acid;-   1-(2-(2,4-dichlorophenoxy)ethyl)-3-(2-methylphenyl)-1H-indole-2-carboxylic    acid;-   1-(3-(2,4-dichlorophenoxy)propyl)-3-(2-methylphenyl)-1H-indole-2-carboxylic    acid;-   1-(4-(2,4-dichlorophenoxy)butyl)-3-(2-methylphenyl)-1H-indole-2-carboxylic    acid;-   3-benzyl-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;-   3-(2-methylbenzyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-methylbenzyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(4-methylbenzyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-naphthylmethyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-(2-phenylethyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-(3-phenylpropyl)-1H-indole-2-carboxylic    acid;-   3-(2-methylphenyl)-1-(2-(1-naphthyloxy)ethyl)-1H-indole-2-carboxylic    acid;-   3-(2-methylphenyl)-1-(2-(2-naphthyloxy)ethyl)-1H-indole-2-carboxylic    acid;-   1-(2-(2,3-dichlorophenoxy)ethyl)-3-(2-methylphenyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-((E)-2-phenylvinyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-((1E)-3-phenylprop-1-enyl)-1H-indole-2-carboxylic    acid;-   3-((E)-2-cyclohexylvinyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-(3-(piperidin-1-ylcarbonyl)phenyl)-1H-indole-2    carboxylic acid;-   3-(4-fluoro-3-(morpholin-4-ylcarbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(((2-methoxyethyl)amino)carbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-((dimethylamino)sulfonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(morpholin-4-ylmethyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-piperidin-1-yl-1H-indole-2-carboxylic    acid;-   3-morpholin-4-yl-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-((3-(trifluoromethoxy)phenyl)amino)-1H-indole-2-carboxylic    acid;-   3-(4-carboxypiperidin-1-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-anilino-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthylthio)cyclohexyl)-1H-indole-2-carboxylic acid;-   3-(3-(1-naphthyloxy)cyclohexyl)-1H-indole-2-carboxylic acid;-   1-(2-methylbenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(2-(dimethylamino)ethyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-methylbenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(4-methylbenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(1,1′-biphenyl-2-ylmethyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(1,1′-biphenyl-3-ylmethyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(1,1′-biphenyl-4-ylmethyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(2,4-dimethylbenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(4-carboxybenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-((2S)-2-methyl-3-(1-naphthyloxy)propyl)-4-(2-methylphenyl)-1H-indole-2-carboxylic    acid;-   1-((2R)-2-methyl-3-(1-naphthyloxy)propyl)-4-(2-methylphenyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthyloxy)propyl)-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxylic    acid;-   3-(3-(1-naphthyloxy)propyl)-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic    acid;-   1-(4-methoxybenzyl)-3-(2-(1-naphthyloxy)ethoxy)-1H-indole-2-carboxylic    acid;-   1-(4-methoxybenzyl)-3-(3-(1-naphthyloxy)prop-1-ynyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2,6-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-4-(2-oxocyclohexyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-3-(morpholin-4-ylmethyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-(pyrrolidin-1-ylmethyl)-1H-indole-2-carboxylic    acid;-   3-((dimethylamino)methyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(((cyclohexylmethyl)amino)methyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-morpholin-4-ylcyclohexyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-(piperidin-1-ylmethyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-3-((4-methylpiperidin-1-yl)methyl)-1-(3-(1-naphthyloxy)propyl)-1    H-indole-2-carboxylic acid;-   3-((benzyl(methyl)amino)methyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-3-((methyl(pyridin-2-ylmethyl)amino)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-3-((methyl(pyridin-3-ylmethyl)amino)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-3-((methyl(pyridin-4-ylmethyl)amino)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-(4-fluorophenyl)cyclohex-1-en-1-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methyl-6-nitrophenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-chloro-6-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-4-(2-(4-nitrophenyl)cyclohex-1-en-1-yl)-1H-indole-2-carboxylic    acid;-   4-(2-(3-methoxyphenyl)cyclohex-1-en-1-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(5-fluoro-2-methyl-3-((methylsulfonyl)methyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-phenyl-1H-indole-2-carboxylic    acid;-   3-bromo-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-3-((4-methylphenyl)amino)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(4-hydroxyphenyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(3-hydroxyphenyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-pyridin-4-yl-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-pyridin-3-yl-1H-indole-2-carboxylic    acid;-   3-cyano-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-bromo-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-(benzyloxy)-1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic    acid;-   5-fluoro-3-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;-   5-fluoro-1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic    acid;-   5-fluoro-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-((3-(trifluoromethoxy)phenyl)amino)-1H-indole-2-carboxylic    acid;-   5-(benzyloxy)-1-(3-(1-naphthyloxy)propyl)-3-((3-(trifluoromethoxy)phenyl)amino)-1H-indole-2-carboxylic    acid;-   5-(benzyloxy)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-(benzyloxy)-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-(tert-butoxymethyl)phenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-fluoro-1-(3-(1-naphthyloxy)propyl)-3-(2-((3-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-indole-2-carboxylic    acid;-   5-chloro-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-chloro-3-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-hydroxy-3-(2-isopropylphenyl)-1-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-hydroxy-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-isopropylphenyl)-5-(4-morpholin-4-ylbutoxy)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   5-fluoro-1-(3-(1-naphthyloxy)propyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic    acid;-   3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-5-phenyl-1H-indole-2-carboxylic    acid;-   3-(2,6-dimethylphenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-5-((1E)-pent-1-enyl)-1H-indole-2-carboxylic    acid;-   3-(2,6-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic    acid;-   3-(2-chlorophenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-((1E)-5-(dimethylamino)pent-1-enyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-((1E)-6-((2-carboxybenzoyl)amino)hex-1-enyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-((1E)-6-aminohex-1-enyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(6-aminohexyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(5-(dimethylamino)pentyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   6-chloro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;-   3-(2-((1E)-5-(dimethylamino)pent-1-enyl)phenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   3-(2-(dimethylamino)phenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic    acid;-   1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;-   1-methyl-5-(4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indol-2-yl)-1H-pyrazol-3-ol;-   4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-2-(1H-tetraazol-5-yl)-1H-indole;    and therapeutically acceptable salts, prodrugs, esters, amides,    salts of prodrugs, salts of esters, and salts of amides thereof.

Still another embodiment pertains to compositions comprising anexcipient and a therapeutically effective amount of a compound havingFormula I.

Still another embodiment pertains to methods for treating mammals havinga disease characterized by overexpression or unregulation of Mcl-1protein comprising administering thereto a therapeutically effectiveamount of a compound having Formula I.

Still another embodiment comprises methods of treating mammals having adisease characterized by overexpression or unregulation of Mcl-1 proteincomprising administering thereto therapeutically effective amounts of acompound having Formula I and one or more than one additionaltherapeutic agents, with or without also administering radiotherapythereto.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties of compounds herein are represented by identifiers(capital letters with numerical and/or alphabetical superscripts) andmay be specifically embodied.

It is meant to be understood that proper valences are maintained for allcombinations herein, that monovalent moieties having more than one atomare attached through their left ends, and that divalent moieties aredrawn from left to right.

It is also meant to be understood that a specific embodiment of avariable moiety may be the same or different as another specificembodiment having the same identifier.

The term “alkenyl,” as used herein, means monovalent, straight orbranched chain hydrocarbon moieties having one or more than onecarbon-carbon double bonds, such as C₂-alkenyl, C₃-alkenyl, C₄-alkenyl,C₅-alkenyl, C₆-alkenyl and the like.

The term “alkenylene,” as used herein, means divalent, straight orbranched chain hydrocarbon moieties having one or more than onecarbon-carbon double bonds, such as C₂-alkenylene, C₃-alkenylene,C₄-alkenylene, C₅-alkenylene, C₆-alkenylene and the like.

The term “alkyl,” as used herein, means monovalent, saturated, straightor branched chain hydrocarbon moieties, such as C₁-alkyl, C₂-alkyl,C₃-alkyl, C₄-alkyl, C₅-alkyl, C₆-alkyl and the like.

The term “alkylene,” as used herein, means divalent, saturated, straightor branched chain hydrocarbon moieties, such as C₁-alkylene,C₂-alkylene, C₃-alkylene, C₄-alkylene, C₅-alkylene, C₆-alkylene and thelike.

The term “alkynyl,” as used herein, means monovalent, straight orbranched chain hydrocarbon moieties having one or more than onecarbon-carbon triple bonds, such as C₂-alkynyl, C₃-alkynyl, C₄-alkynyl,C₅-alkynyl, C₆-alkynyl and the like.

The term “alkynylene,” as used herein, means divalent, straight orbranched chain hydrocarbon moieties having one or more than onecarbon-carbon triple bonds, such as C₂-alkynylene, C₃-alkynylene,C₄-alkynylene, C₅-alkynylene, C₆-alkynylene and the like.

The term “C(O)OH bioisostere, as used herein, means a moiety with asubstantially similar physical or chemical property that imparts similarbiological properties to the compound having Formula (I). Examples ofC(O)OH bioisosteres include monovalent radicals derived from removal ofone hydrogen atom from a molecule such as isothiazol-3(2H)-one1,1-dioxide, isothiazolidin-3-one 1,1-dioxide,1,2,4-oxadiazol-5(2H)-one, 1,2,5-thiadiazolidin-3-one 1,1-dioxide,1,2,5-thiadiazol-3-ol, 1,2,4-oxadiazolidine-3,5-dione, 2H-tetraazole andthe like.

The term “cycloalkane,” as used herein, means saturated cyclic orbicyclic hydrocarbon moieties, such as C₄-cycloalkane, C₅-cycloalkane,C₆-cycloalkane, C₇-cycloalkane, C₈-cycloalkane, C₉-cycloalkane,C₁₀-cycloalkane, C₁₁-cycloalkane, C₁₂-cycloalkane and the like.

The term “cycloalkyl,” as used herein, means monovalent, saturatedcyclic and bicyclic hydrocarbon moieties, such as C₃-cycloalkyl,C₄-cycloalkyl, C₅-cycloalkyl, C₆-cycloalkyl, C₇-cycloalkyl,C₈-cycloalkyl, C₉-cycloalkyl, C₁₀-cycloalkyl, C₁₁-cycloalkyl,C₁₂-cycloalkyl and the like.

The term “cycloalkene,” as used herein, means cyclic and bicyclichydrocarbon moieties having one or more than one carbon-carbon doublebonds, such as C₅-cycloalkene, C₆-cycloalkene, C₇-cycloalkene,C₈-cycloalkene, C₉-cycloalkene, C₁₀-cycloalkene, C₁₁-cycloalkene,C₁₂-cycloalkene and the like.

The term “cycloalkenyl,” as used herein, means monovalent, cyclichydrocarbon moieties having one or more than one carbon-carbon doublebonds, such as C₄-cycloalkenyl, C₅-cycloalkenyl, C₆-cycloalkenyl,C₇-cycloalkenyl, C₈-cycloalkenyl, C₉-cycloalkenyl, C₁₀-cycloalkenyl,C₁₁-cycloalkenyl, C₁₂-cycloalkenyl and the like.

The term “heteroarene,” as used herein, means furan, imidazole,isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole,1,3,4-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, thiophene, triazineand 1,2,3-triazole.

The term “heteroaryl,” as used herein, means furanyl, imidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,1,2,3-thiadiazoyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiophenyl,triazinyl and 1,2,3-triazolyl.

The term “heterocycloalkane,” as used herein, means cycloalkane havingone or two or three CH₂ moieties replaced with independently selected O,S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N and also means cycloalkane having one or two or three CH₂moieties unreplaced or replaced with independently selected O, S, S(O),SO₂ or NH and one or two CH moieties replaced with N.

The term “heterocycloalkene,” as used herein, means cycloalkene havingone or two or three CH₂ moieties replaced with independently selected O,S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N and also means cycloalkene having one or two or three CH₂moieties unreplaced or replaced with independently selected O, S, S(O),SO₂ or NH and one or two CH moieties replaced with N.

The term “heterocycloalkyl,” as used herein, means cycloalkyl having oneor two or three CH₂ moieties replaced with independently selected O, S,S(O), SO₂ or NH and one or two CH moieties unreplaced or replaced with Nand also means cycloalkyl having one or two or three CH₂ moietiesunreplaced or replaced with independently selected O, S, S(O), SO₂ or NHand one or two CH moieties replaced with N.

The term “heterocycloalkenyl,” as used herein, means cycloalkenyl havingone or two or three CH₂ moieties replaced with independently selected O,S, S(O), SO₂ or NH and one or two CH moieties unreplaced or replacedwith N and also means cycloalkenyl having one or two or three CH₂moieties unreplaced or replaced with independently selected O, S, S(O),SO₂ or NH and one or two CH moieties replaced with N.

The term “cyclic moiety,” as used herein, means benzene, cycloalkane,cycloalkyl, cycloalkene, cycloalkenyl, heteroarene, heteroaryl,heterocycloalkane, heterocycloalkyl, heterocycloalkene,heterocycloalkenyl, phenyl and spiroalkyl.

Compounds of this invention may contain asymmetrically substitutedcarbon atoms in the R or S configuration, wherein the terms “R” and “S”are as defined in Pure Appl. Chem. (1976) 45, 13-10. Compounds havingasymmetrically substituted carbon atoms with equal amounts of R and Sconfigurations are racemic at those atoms. Atoms having excess of oneconfiguration over the other are assigned the configuration in excess,preferably an excess of about 85%-90%, more preferably an excess ofabout 95%-99%, and still more preferably an excess greater than about99%. Accordingly, this invention is meant to embrace racemic mixtures,relative and absolute diastereoisomers and the compounds thereof.

Compounds of this invention may also contain carbon-carbon double bondsor carbon-nitrogen double bonds in the Z or E configuration, in whichthe term “Z” represents the larger two substituents on the same side ofa carbon-carbon or carbon-nitrogen double bond and the term “E”represents the larger two substituents on opposite sides of acarbon-carbon or carbon-nitrogen double bond. The compounds of thisinvention may also exist as a mixture of “Z” and “E” isomers.

Compounds of this invention containing NH, C(O)H, C(O)OH, C(O)NH₂, OH orSH moieties may have attached thereto prodrug-forming moieties. Theprodrug-forming moieties are removed by metabolic processes and releasethe compounds having the freed NH, C(O)H, C(O)OH, C(O)NH₂, OH or SH invivo. Prodrugs are useful for adjusting such pharmacokinetic propertiesof the compounds as solubility and/or hydrophobicity, absorption in thegastrointestinal tract, bioavailability, tissue penetration, and rate ofclearance.

Metabolites of compounds having Formula I, produced by in vitro or invivo metabolic processes, may also have utility for treating diseasescaused or exacerbated by overexpressed or unregulated Mcl-1 protein.

Certain precursor compounds of compounds having Formula I may bemetabolized in vitro or in vivo to foam compounds having Formula I andmay thereby also have utility for treating diseases caused orexacerbated by overexpressed or unregulated Mcl-1 protein.

Compounds having Formula I may exist as acid addition salts, basicaddition salts or zwitterions. Salts of compounds having Formula I areprepared during their isolation or following their purification. Acidaddition salts are those derived from the reaction of a compound havingFormula I with acid. Accordingly, salts including the acetate, adipate,alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, formate, fumarate, glycerophosphate, glutamate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate,methanesulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, phosphate, picrate, propionate, succinate,tartrate, thiocyanate, trichloroacetic, trifluoroacetic,para-toluenesulfonate and undecanoate salts of the compounds havingFormula I are meant to be embraced by this invention. Basic additionsalts of compounds are those derived from the reaction of the compoundshaving Formula I with the bicarbonate, carbonate, hydroxide or phosphateof cations such as lithium, sodium, potassium, calcium and magnesium.

Compounds having Formula I may be administered, for example, bucally,ophthalmically, orally, osmotically, parenterally (intramuscularly,intraperitoneally intrasternally, intravenously, subcutaneously),rectally, topically, transdermally and vaginally.

Therapeutically effective amounts of a compound having Formula I dependon recipient of treatment, disease treated and severity thereof,composition comprising it, time of administration, route ofadministration, duration of treatment, potency, rate of clearance andwhether or not another drug is co-administered. The amount of a compoundhaving Formula I used to make a composition to be administered daily toa patient in a single dose or in divided doses is from about 0.001 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula I may be administered with or without anexcipient. Excipients include, for example, encapsulators and additivessuch as absorption accelerators, antioxidants, binders, buffers, coatingagents, coloring agents, diluents, disintegrating agents, emulsifiers,extenders, fillers, flavoring agents, humectants, lubricants, perfumes,preservatives, propellants, releasing agents, sterilizing agents,sweeteners, solubilizers, wetting agents and mixtures thereof.

Compounds having Formula I may be radiolabeled with a radioactiveisotope such as carbon (i.e. ¹³C), hydrogen (i.e. ³H), nitrogen (i.e.¹⁵N), phosphorus (i.e. ³²P), sulfur (i.e. ³⁵S), iodide (i.e. ¹²⁵I) andthe like. Radioactive isotopes may be incorporated into the compoundshaving Formula I by reacting the same and a radioactive derivitizingagent or by incorporating a radiolabeled intermediate into theirsyntheses. The radiolabeled compounds of Formula I are useful for bothprognostic and diagnostic applications and for in vivo and in vitroimaging.

Compounds having Formula I may be incorporated into devices such as, butnot limited to, arterio-venous grafts, biliary stents, by-pass grafts,catheters, central nervous system shunts, coronary stents, drug deliveryballoons, peripheral stents and ureteural stents, each of which may beused in areas such as, but not limited to, the vasculature forintroduction of a compound having Formula I into selected tissues ororgans in the body. One measure of the effectiveness of compounds havingFormula I is reduction or elimination of device-associated thrombi andcomplications associated therewith.

Compounds having Formula I can used as a radiosensitizers which enhancethe efficacy of radiotherapy. Examples of radiotherapy include, but arenot limited to, external beam radiotherapy, teletherapy, brachytherapyand sealed and unsealed source radiotherapy.

Excipients for preparation of compositions comprising a compound havingFormula I to be administered orally include, for example, agar, alginicacid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butyleneglycol, carbomers, castor oil, cellulose, cellulose acetate, cocoabutter, corn starch, corn oil, cottonseed oil, cross-povidone,diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate,fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil,hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose,magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides,olive oil, peanut oil, potassium phosphate salts, potato starch,povidone, propylene glycol, Ringer's solution, safflower oil, sesameoil, sodium carboxymethyl cellulose, sodium phosphate salts, sodiumlauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearylfumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfurylalcohol, triglycerides, water and mixtures thereof. Excipients forpreparation of compositions comprising a compound having Formula I to beadministered ophthalmically or orally include, for example, 1,3-butyleneglycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid estersof sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil,polyethylene glycols, propylene glycol, sesame oil, water and mixturesthereof. Excipients for preparation of compositions comprising acompound having Formula I to be administered osmotically include, forexample, chlorofluoro-hydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound havingFormula I to be administered parenterally include, for example,1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germoil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil,Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. orisotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound havingFormula I to be administered rectally or vaginally include, for example,cocoa butter, polyethylene glycol, wax and mixtures thereof.

Assay

(Fam)-NoxaCF (6-FAM)-GELEVEFATQLRRFGDKLNF-amide) (SEQ. ID. NO. 1) wasmade on a 433A automated synthesizer (Applied Biosystems, Foster City,Calif.) using standard Fastmoc™ deprotection/coupling cycles with 0.25mmol MBHA Rink amide resin (SynPep, Dublin, Calif.). Cartridgescontaining N^(α)-Fmoc-amino acids (1 mmol) with side-chain protection(Arg: 2,2,5,7,8-pentamethylchroman-6-sulfonyl; Asp and Glu: tert-butylester; Asn, Cys, Gln, and His: trityl; Lys and Trp:tert-butyloxycarbonyl; Ser, Thr, and Tyr: tert-butyl ether wereactivated with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (1 mmol), 1-hydroxybenzotriazole (1 mmol) anddiisopropylethylamine (2 mmol) in N-methylpyrrolidone (NMP). Theactivated amino acid was coupled for 30 minutes following removal of theN-terminal Fmoc group with 20% piperidine in NMP. Labeling wasaccomplished by suspending the resin-bound, N-terminally deprotectedside-chain protected peptide resin (0.04 mmol) and6-carboxyfluorescein-NHS ester (57 mg) in anhydrous dimethylformamide (2mL) containing 0.02 mL diisopropylethylamine (DIEA) and shaking atambient temperature overnight. The resin was drained, washed 3 timeswith 1:1 dichloromethane/methanol and dried. The labeled resin wascleaved and deprotected by mixing withTFA:water:thioanisole:phenol:3,6-dioxa-1,8-octanedithiol:triisopropylsilane,80:5:5:5:2.5:2.5 for 3 hours at ambient temperature. Followingevaporation under reduced pressure, the crude peptide was recovered byprecipitation with ether. The product was purified on a preparative HPLCrunning Unipoint® analysis software (Gilson, Inc., Middleton, Wis.) on a25 mm×200 mm radial compression column containing Delta-Pak® C₁₈ packing(Waters, Inc., Taunton, Mass.) with a flow rate of 20 mL/min. Thepeptides were eluted with a linear gradient of 0.1% TFA/water andacetonitrile. Fractions containing the product were combined andlyophilized. The purity of the final products were confirmed byreverse-phase analytical HPLC on a Hewlett-Packard 1050 series systemwith diode-array and fluorescence detection (Agilent Technologies, PaloAlto, Calif.) eluted with a linear gradient of 0.1% trifluoroaceticacid/water and acetonitrile on a 4.6×250 mm YMC ODS-AQ, 5 μm, 120 Åcolumn (Waters Inc.) to give the product (45.6 mg) as a yellow powderfollowing lyophilization. The identity of the product was confirmed bymatrix-assisted laser desorption ionization mass spectrography(MALDI-MS) on a Voyager DE-PRO (Applied Biosystems), m/z 1470.00 and1448.01 (M+H)⁺.

A fluorescence polarization assay was used for IC₅₀ determination ofrepresentative compounds having Formula I against recombinant Mcl-1protein. Compounds were series diluted in DMSO starting at 10 μM andtransferred (5 μL) into a 96 well plate. Then, 120 μL of a mixturecontaining 10 nM fluorescent Noxa BH3 peptide and 80 nM Mcl-1 proteinwas added to each well. For each assay, free peptide controls(fluorescent peptide only) and bound peptide controls (fluorescentpeptide in the presence of Mcl-1) were included on each assay plate. Theplate was mixed on a shaker for 1 minute and incubated at roomtemperature for an additional 15 minutes. The polarization (in mP) wasmeasured at room temperature with excitation wavelength at 485 nm andemission wavelength at 530 nm using an Analyst (LJL, Molecular Dynamic,Sunnyvale, Calif.). The percentage inhibition was calculated by %inhibition=100×(1−(mP−mP_(f))/(mP_(b)−mP_(f))) in which mP_(f) is thefree peptide control and mP_(b) is the bound peptide control. Based onpercentage of inhibition, the IC₅₀ (inhibitor concentration at which 50%of bound peptide is displaced), obtained by fitting the inhibition datausing Prism 3.0 software (Graphpad Software Inc, San Diego, Calif.). Theresults are shown in TABLE 1.

TABLE 1 IC₅₀'s (in μM) For Representative CompoundsHaving Formula I ForInhibition of Mcl-1 Protein <0.030 <0.030 <0.030 <0.030 0.031 0.0330.034 0.037 0.039 0.045 0.055 0.059 0.064 0.066 0.069 0.070 0.073 0.0750.078 0.079 0.085 0.085 0.088 0.090 0.092 0.097 0.099 0.102 0.104 0.1090.109 0.114 0.126 0.131 0.135 0.137 0.142 0.143 0.144 0.146 0.149 0.1500.158 0.169 0.169 0.191 0.204 0.212 0.219 0.222 0.223 0.233 0.237 0.2520.252 0.256 0.272 0.281 0.285 0.286 0.292 0.306 0.326 0.332 0.337 0.3370.346 0.346 0.351 0.351 0.366 0.380 0.387 0.391 0.414 0.416 0.418 0.4400.445 0.453 0.504 0.507 0.507 0.509 0.522 0.528 0.530 0.542 0.549 0.5540.555 0.558 0.570 0.600 0.604 0.621 0.630 0.637 0.661 0.666 0.674 0.7090.731 0.759 0.764 0.777 0.798 0.800 0.829 0.840 0.881 0.889 0.897 0.9080.933 0.973 1.022 1.046 1.140 1.150 1.205 1.248 1.260 1.410 1.446 1.4711.765 1.830 1.879 1.961 2.069 2.072 2.299 2.316 2.418 2.453 2.826 3.0333.133 3.459 3.483 3.517 3.627 3.801 4.048 4.237 4.588 4.746 5.095 5.2985.396 5.576 5.886 6.170 6.934 6.949 7.296 7.377 9.644 9.911 10.138

These data demonstrate the utility of representative compounds havingFormula I as inhibitors of the activity of Mcl-1 protein.

These data demonstrate the utility of representative compounds havingFormula I as inhibitors of the activity of Mcl-1 protein.

Accordingly, compounds having Formula I are expected to have utility intreatment of diseases during which anti-apopotic Mcl-1 is expressed andalso utility in treatment of diseases in which anti-apopotic familyprotein members having close structural homology to Mcl-1 such as, forexample, Bcl-X_(L) protein, Bcl-2 protein and Bcl-w protein areexpressed.

Overexpression of Mcl-1 correlates with resistance to chemotherapy,clinical outcome, disease progression, overall prognosis or acombination thereof in various hematologic and solid tumor types such asacoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acutemyelogenous leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer (including estrogen-receptorpositive breast cancer), bronchogenic carcinoma, cervical cancer,chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chroniclymphocytic leukemia, chronic myelocytic (granulocytic) leukemia,chronic myleogeneous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, gastric carcinoma, germ celltesticular cancer, gestational trophobalstic disease, glioblastoma, headand neck cancer, heavy chain disease, hemangioblastoma, hepatoma,hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, liposarcoma, lung cancer (including small cell lungcancer and non-small cell lung cancer), lymphagioendothelio-sarcoma,lymphangiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, includingDiffuse Large B-cell lymphoma, follicular lymphoma Hodgkin's lymphomaand non-Hodgkin's lymphoma), malignancies and hyperproliferativedisorders of the bladder, breast, colon, lung, ovaries, pancreas,prostate, skin and uterus, lymphoid malignancies of T-cell or B-cellorigin, leukemia, lymphoma, medullary carcinoma, medulloblastoma,melanoma, meningioma, mesothelioma, multiple myeloma, myelogenousleukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lungcancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovariancancer, pancreatic cancer, papillary adenocarcinomas, papillarycarcinoma, peripheral T-cell lymphoma, pinealoma, polycythemia vera,prostate cancer (including hormone-insensitive (refractory) prostatecancer), rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, testicular cancer(including germ cell testicular cancer) thyroid cancer, Waldenström'smacroglobulinemia, testicular tumors, uterine cancer, Wilms' tumor andthe like.

It is also expected that compounds having Formula I would inhibit growthof cells derived from a pediatric cancer or neoplasm including embryonalrhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatricacute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma,pediatric anaplastic ependymoma, pediatric anaplastic large celllymphoma, pediatric anaplastic medulloblastoma, pediatric atypicalteratoid/rhabdoid tumor of the central nervous system, pediatricbiphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatriccancers of Ewing's family of tumors such as primitive neuroectodermalrumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorablehistology Wilm's tumor, pediatric glioblastoma, pediatricmedulloblastoma, pediatric neuroblastoma, pediatricneuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers(such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidneytumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such aslymphoma and skin cancer and the like.

Involvement of Mcl-1 in acute lymphoblastic leukemia is reported inBlood 1998, 91, 991-1000.

Involvement of Mcl-1 in acute myelogenous leukemia is also reported inBlood 1998, 91, 991-1000.

Involvement of Mcl-1 in cervical cancer is reported in Cancer Letters(Shannon, Ireland) 2002, 180, 63-68.

Involvement of Mcl-1 in chronic lymphocytic leukemia is reported inJournal of the National Cancer Institute 2004, 96, 673-682 andImmunology 2005, 114, 441-449.

Involvement of Mcl-1 in colorectal cancer, is reported in Annals ofoncology: Official Journal of the European Society for MedicalOncology/ESMO 2001, 12, 779-785.

Involvement of Mcl-1 in gastric carcinoma, is reported in Gastric Cancer2004, 7, 78-84.

Involvement of Mcl-1 in gestational trophobalstic disease is reported inCancer 2005, 103, 268-276.

Involvement of Mcl-1 in glioblastoma is reported in Journal ofNeurology, Neurosurgery, and Psychiatry 1999, 67, 763-768.

Involvement of Mcl-1 in head and neck cancer is reported in Archives ofOtolaryngology-Head and Neck Surgery 1999, 125, 417-422.

Involvement of Mcl-1 in lung cancer is reported in Pathology OncologyResearch: POR 1999, 5, 179-186.

Involvement of Mcl-1 in mesothioloma, is reported in Clinical CancerResearch 1999, 5, 3508-3515.

Involvement of Mcl-1 in multiple myeloma is reported in European Journalof Immunology 2004, 34, 3156-3164.

Involvement of Mcl-1 in non-Hodgkin's lymphoma is reported in BritishJournal of Haematology 2002, 116, 158-161.

Involvement of Mcl-1 in oligodendroglioma is reported in Cancer (NewYork) 1999, 86, 1832-1839.

Involvement of Mcl-1 in ovarian cancer is reported in Journal ofClinical Oncology: Official Journal of the American Society of ClinicalOncology 2000, 18, 3775-3781.

Involvement of Mcl-1 in pancreatic cancer is reported in Oncology 2002,62, 354-362.

Involvement of Mcl-1 in peripheral T-cell lymphoma is reported inJournal of Pathology 2003, 200, 240-248.

Compounds having Formula I are expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, aurora kinase inhibitors, Bcl-2 familyprotein (for example, Bcl-xL, Bcl-2, Bcl-w, Bfl-1) inhibitors, Bcr-Ablkinase inhibitors, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemiaviral oncogene homolog (ErbB2) receptor inhibitors, growth factorinhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase(HDAC) inhibitors inhibitors, hormonal therapies, immunologicals,intercalating antibiotics, kinase inhibitors, mammalian target ofrapomycin inhibitors, mitogen-activated extracellular signal-regulatedkinase inhibitors, non-steroidal anti-inflammatory drugs (NSAID's),platinum chemotherapeutics, polo-like kinase inhibitors, proteasomeinhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinaseinhibitors, retinoids/deltoids plant alkaloids, topoisomerase inhibitorsand the like.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, Cloretazine™ (VNP 40101M), cyclophosphamide, decarbazine,estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine(CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine,nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa,treosulfan, trofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and thelike.

Bcl protein family member inhibitors include AT-101 ((−)gossypol),GENASENSE® (G3139 or oblimersen (Bcl-2-targeting antisenseoglionucleotide)), IPI-194, IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX™ (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFr immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),Herceptin® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, ASHER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB®,NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam) ibuprofen cream, ALEVE® andNAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin),CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL®(ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™, axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, Macugen(pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034),(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap,vatalanib, ZACTIMA™ (vandetanib, ZD-6474) and the like.

Antimetabolites include ALIMTA® (premetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR,enocitabine, ethylcytidine, fludarabine, hydroxyurea, 5-fluorouracil(5-FU) alone or in combination with leucovorin, GEMZAR® (gemcitabine),hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurineriboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed,ocfosate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine,trimetrexate, S-1, tiazofurin, tegafur, TS-1, vidarabine, UFT and thelike.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (doxorubicin), elsamitrucin, epirbucin,glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL®, (flutamide), EVISTA® (raloxifene), fadrozole,FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®, (letrozole),formestane, glucocorticoids, HECTOROL® or RENAGEL® (doxercalciferol),lasofoxifene, leuprolide acetate, MEGACE® (megesterol), MIFEPREX®(mifepristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen citrate),PLENAXIS™ (abarelix), predisone, PROPECIA® (finasteride), rilostane,SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone(LHRH)), vantas, VETORYL®, (trilostane or modrastane), ZOLADEX®(fosrelin, goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b), interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,BAM-002, BEROMUN® (tasonermin), BEXXAR® (tositumomab), CamPath®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine,denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocytealpha interferon, imiquimod, MDX-010, melanoma vaccine, mitumomab,molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim),OncoVAC-CL, OvaRex® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE®,sargaramostim, sizofilan, teceleukin, TheraCys®, ubenimex, VIRULIZIN®,Z-100, WF-10, PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX®(daclizumab), ZEVALIN® (90Y-Ibritumomab tiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth,or differentiation of tissue cells to direct them to have anti-tumoractivity and include include krestin, lentinan, sizofuran, picibanilPF-3512676 (CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881, vinflunine, ZK-EPO and the like.

Compounds of the present invention are also intended to be used as aradiosensitizer that enhances the efficacy of radiotherapy. Examples ofradiotherapy include, but are not limited to, external beamradiotherapy, teletherapy, brachtherapy and sealed and unsealed sourceradiotherapy.

Additionally, compounds having Formula I may be combined with otherchemptherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN®, ALTOCOR® or MEVACOR® (lovastatin),AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN™ (exisulind),AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE® (tazarotne), AVE-8062,BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor),canvaxin (vaccine), CeaVac™ (cancer vaccine), CELEUK® (celmoleukin),CEPLENE® (histamine dihydrochloride), CERVARIX™ (human papillomavirusvaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin);

O: Vincristine (ONCOVIN®); P: prednisone), CyPat™, combrestatin A4P,DAB(389)EGF or TransMID-107R™ (diphtheria toxins), dacarbazine,dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil,EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposome lotion),discodermolide, DX-8951f (exatecan mesylate), enzastaurin, EPO906,GARDASIL® (quadrivalent human papillomavirus (Types 6, 11, 16, 18)recombinant vaccine), gastrimmune, genasense, GMK (ganglioside conjugatevaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin,hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR(cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-α,interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib,5,10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine),NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT®(pentostatin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® (melanomavaccine treatment), OncoVAX (IL-2 Vaccine), ORATHECIN™ (rubitecan),OSIDEM® (antibody-based cell drug), OvaRex® MAb (murine monoclonalantibody), paditaxel, PANDIMEX™ (aglycone saponins from ginsengcomprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol(aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine),pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat,REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral),SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine(Streptomyces staurospores), talabostat (PT100), TARGRETIN®(bexarotene), Taxoprexin® (DHA-paclitaxel), TELCYTA™ (TLK286),temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide,THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFerade™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS™ (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), zometa(zolendronic acid), zorubicin and the like.

It is also expected that compounds having Formula I would inhibit growthof cells derived from a pediatric cancer or neoplasm including embryonalrhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatricacute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma,pediatric anaplastic ependymoma, pediatric anaplastic large celllymphoma, pediatric anaplastic medulloblastoma, pediatric atypicalteratoid/rhabdoid tumor of the central nervous system, pediatricbiphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatriccancers of Ewing's family of tumors such as primitive neuroectodermalrumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorablehistology Wilm's tumor, pediatric glioblastoma, pediatricmedulloblastoma, pediatric neuroblastoma, pediatricneuroblastoma-derived myelocytomatosis, pediatric pre-B-cell cancers(such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidneytumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such aslymphoma and skin cancer and the like (commonly-owned U.S. applicationSer. No. 10/988,338), Cancer Res., 2000, 60, 6101-10); and autoimmunedisorders include, acquired immunodeficiency disease syndrome,autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatorydiseases, thrombocytopenia and the like (Current Allergy and AsthmaReports 2003, 3:378-384; Br. J. Haematol. 2000 September; 110(3):584-90; Blood 2000 Feb. 15; 95(4):1283-92; and New England Journal ofMedicine 2004 September; 351(14): 1409-1418).

Compounds having Formula I may be made by synthetic chemical processes,examples of which are shown hereinbelow. It is meant to be understoodthat the order of the steps in the processes may be varied, thatreagents, solvents and reaction conditions may be substituted for thosespecifically mentioned, and that vulnerable moieties such as C(O)OH,C(O) and C(O)H, NH, C(O)NH₂, OH and SH moieties may be protected anddeprotected, as necessary.

Protecting groups for C(O)OH moieties include, but are not limited to,acetoxymethyl, allyl, benzoylmethyl, benzyl, benzyloxymethyl,tert-butyl, tert-butyldiphenylsilyl, diphenylmethyl, cyclobutyl,cyclohexyl, cyclopentyl, cyclopropyl, diphenylmethylsilyl, ethyl,para-methoxybenzyl, methoxymethyl, methoxyethoxymethyl, methyl,methylthiomethyl, naphthyl, para-nitrobenzyl, phenyl, n-propyl,2,2,2-trichloroethyl, triethylsilyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, triphenylmethyl and the like.

Protecting groups for C(O) and C(O)H moieties include, but are notlimited to, 1,3-dioxylketal, diethylketal, dimethylketal,1,3-dithianylketal, O-methyloxime, O-phenyloxime and the like.

Protecting groups for NH moieties include, but are not limited to,acetyl, alanyl, benzoyl, benzyl (pheriylmethyl), benzylidene,benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc),3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl,formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl,phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl,trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl,para-toluenesulfonyl and the like.

Protecting groups for OH and SH moieties include, but are not limitedto, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl,benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,3,4-dimethoxybenzyl, 3,4-dimethoxybenzyloxycarbonyl,1,1-dimethyl-2-propenyl, diphenylmethyl, methanesulfonyl, methoxyacetyl,4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl,para-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl,2-(trimethylsilyl)ethoxycarbonyl, 2-trimethylsilylethyl,triphenylmethyl, 2-(triphenylphosphonio)ethoxycarbonyl and the like.

A discussion protecting groups is provided in T. H. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York (1999).

The following abbreviations have the meanings indicated.

ADDP means 1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃ and K₂SO₄); 9-BBN means9-borabicyclo(3.3.1)nonane; (DHQD)₂PHAL means hydroquinidine1,4-phthalazinediol diethyl ether; DBU means1,8-diazabicyclo(5.4.0)undec-7-ene; DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; d means1,1-bis(diphenylphosphino)methane; EDAC means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; Fmoc meansfluorenylmethoxycarbonyl; HATU meansO-(7-azabenzotriazol-1-yl)-N,N′N′N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporous triethylammoniummethylpolystyrene cyanoborohydride; PyBOP meansbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; TEAmeans triethylamine; TFA means trifluoroacetic acid; THF meanstetrahydrofuran; NCS means N-chlorosuccinimide; NMM meansN-methylmorpholine; NMP means N-methylpyrrolidine and PPh₃ meanstriphenylphosphine.

As shown in SCHEME 1, compounds of Formula (1) can be converted tocompounds of Formula (2) by reacting the former with sodium nitrate andan aqueous acid followed by the addition of aqueous sodium acetate andan appropriate 2-oxocycloalkylester.

Examples of acids include hydrochloric acid and the like.

Examples of appropriate 2-oxocycloalkylesters include ethyl2-oxocyclohexanecarboxylate, ethyl 2-oxocyclopentanecarboxylate and thelike.

The reaction is initially conducted at about 0° C., over about 30minutes to about one hour, and then warmed to between about 15° C. and25° C. for about one to four hours, in water.

Compounds of Formula (2) can be converted to compounds of Formula (3) byreacting the former with a solution of borane.

The reaction is typically conducted at ambient temperature over about 8hours to about 20 hours in a solvent such as but not limited to THF.

Compounds of Formula (3) can be converted to compounds of Formula (4) byreacting the former with R⁵OH, triphenylphosphine, and a reagent such asbut not limited to DEAD or TBAD.

The addition is typically conducted below room temperature beforewarming to ambient temperature for about 8-72 hours in a solvent such asbut not limited to THF.

Introduction of moieties represented by D¹, E¹ and F¹ can beaccomplished by reacting substituted anilines of Formula (I) as shown inSCHEME (1). Alternatively, bromoanilines of Formula (1) can be reactedas shown in SCHEME (1) and then subsequently reacted using methodsdescribed in the literature (such as those described in PalladiumReagents And Catalysts: New Perspectives For The 21st Century, By J.Tsuji, John Wiley & Sons, Ltd., Chichester, 2004, 1-670) and known bythose skilled in the art for palladium catalyzed carbon cross couplingreactions.

As shown in SCHEME 2, compounds of Formula (4) can be converted tocompounds of Formula (5) by reacting the former with a base followed byan appropriate compound of Formula B¹Br (5a) or B¹Cl (5b).

Examples of a base include sodium hydride, potassium carbonate and thelike.

Examples of appropriate compounds of Formula (5a) include1-(3-bromopropoxy)naphthalene and the like.

Examples of appropriate compounds of Formula (5b) include2-chloro-1-morpholinoethanone and the like.

The reaction is typically conducted at or below ambient temperature forabout 15 minutes to one hour during the addition of the base, and thenfrom about 20° C. to 80° C. for about one to eight hours after theaddition of the compound of Formula (5a) or (5b) in a solvent such asbut not limited to DMF.

Compounds of Formula (5) can be converted to compounds of Formula (6) byreacting the former with a base.

Examples of bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide and the like.

The reaction is typically conducted over about 1 hour to about 48 hours,between about 0° C. and 35° C., in solvents such as water, methanol,ethanol, isopropanol, mixtures thereof and the like.

Compounds of Formula (4), wherein B¹ is H, can be converted to compoundsof Formula (6) by reacting the former with a base.

Examples of bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide and the like.

The reaction is typically conducted over about 1 hour to about 48 hours,between about 0° C. and 35° C., in solvents such as water, methanol,ethanol, isopropanol, mixtures thereof and the like.

As shown in SCHEME 3, compounds of Formula (3) can be converted tocompounds of Formula (7) by reacting the former with a base followed bymethanesulfonyl chloride.

Examples of bases include TEA, pyridine and the like.

The reaction is typically conducted over about 30 minutes to about threehours, between about 0° C. and 20° C., in acetonitrile.

Compounds of Formula (7) can be converted to compounds of Formula (8) byreacting the former with a compound of Formula R⁵SH, and a base.

Examples of bases include potassium carbonate and sodium carbonate.

The reaction is typically conducted over one to five days between about50° C. and 100° C., in a solvent such as but not limited toacetonitrile.

Compounds of Formula (8) can be converted to compounds of Formula (9) asdescribed in SCHEME 2 for the conversion of compounds of Formula (4) tocompounds of Formula (6).

As shown in SCHEME 4, compounds of Formula (10) can be converted tocompounds of Formula (12) by reacting the former with compounds ofFormula (11), triphenylphosphine, and a reagent such as but not limitedto DEAD or TBAD.

The addition may be conducted below room temperature before warming toambient temperature for about 8-72 hours in a solvent such as but notlimited to THF.

As shown in SCHEME 5, compounds of Formula (12) can be converted tocompounds of Formula (14) by reacting the former, a compound of Formula(13) and a base.

Examples of bases include sodium hydride and potassium carbonate.

The reaction is typically conducted at or below ambient temperature forabout 15 minutes to one hour during the addition of the base, and thenfrom about 20° C. to 80° C. for about one to eight hours after theaddition of the compound of Formula (13) in a solvent such as but notlimited to DMF.

Compounds of Formula (14) can be converted to compounds of Formula (15)using methods described in the literature (such as those described inPalladium Reagents And Catalysts: New Perspectives For The 21st Century,By J. Tsuji, John Wiley & Sons, Ltd., Chichester, 2004, 1-670) and knownby those skilled in the art for palladium catalyzed carbon crosscoupling reactions.

Compounds of Formula (15) can be converted to compounds of Formula (16)as described in SCHEME 2 for the conversion of compounds of Formula (4)to compounds of Formula (6).

As shown in SCHEME 6, compounds of Formula (3) can be converted tocompounds of Formula (16) by reacting the former, iodine,triphenylphosphine and imidazole, followed by a base.

Examples of bases include sodium carbonate and the like.

The reaction is typically conducted from about −10° C. to about 10° C.for about 15 minutes to one hour and then continued for an additional 30minutes to one hour after addition of the base, in a solvent such as butnot limited to dichloromethane.

Compounds of Formula (16) can be converted to compounds of Formula (17)by reacting the former and triphenylphosphine.

The reaction is typically conducted over about 8 to about 48 hours atreflux, in a solvent such as but not limited to acetonitrile ordichloromethane.

Compounds of Formula (17) can be converted to compounds of Formula (18)by reacting the former, a base, and a compound of Formula R⁵C(O)H.

Examples of bases include sodium hydride and n-butyllithium.

The reaction is initially conducted over about one hour at about 60° C.to about 100° C. after the addition of the base and then cooled to about10° C. to about 25° C. and treated with a compounds of Formula (17).After about 10 minutes to about 20 minutes, the compound of FormulaR⁵C(O)H is added and the mixture is again heated at about 60° C. toabout 100° C. for about one to eight hours.

Compounds of Formula (18) can be converted to compounds of Formula (19)by reacting the former with a hydrogen source and a catalyst.

Examples of hydrogen sources include hydrazine and hydrogen gas.

Examples of catalysts include Pd/C and Raney Nickel and the like.

Temperature and pressure vary depending on the hydrogenation method andthe substrates employed. Typical solvents include methanol, ethanol,ethyl acetate, and the like.

Compounds of Formula (19) can be converted to compounds of Formula (20)as described in SCHEME 2 for the conversion of compounds of Formula (4)to compounds of Formula (6).

As shown in SCHEME 7, compounds of Formula (3) can be converted tocompounds of Formula (21) by reacting the former, DMSO, a base, and adehydration agent.

Examples of bases include triethylamine, diisopropylamine, and the like.

Examples of dehydration agents include oxalyl chloride, trifluoroaceticanhydride, and pyridine sulfate.

The reaction is typically conducted over about one to about eight hoursat about −60° C. to about 0° C. depending on the substrate and methodemployed.

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention.

Example 1 3-(3-cyclohexylpropyl)-1H-indole-2-carboxylic acid Example 23-(4-cyclohexylbutyl)-1H-indole-2-carboxylic acid Example 3A ethyl3-(3-hydroxypropyl)-1H-indole-2-carboxylate

To a mixture of ethyl 3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate(2.82 g) in THF (40 mL) was added 1M borane.THF (40 mL). The mixture wasstirred at room temperature for 16 hours, quenched with methanol (100mL) and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 5-25% ethyl acetate/hexanes.

Example 3B ethyl 3-(3-(3-chlorophenoxy)propyl)-1H-indole-2-carboxylate

A mixture of 3-chlorophenol (0.050 g), EXAMPLE 3A (0.052 g),di-tert-butyl azidocarboxylate (0.086 g) and triphenylphosphine (0.1 g)in THF (2.5 mL) was stirred at room temperature for 24 hours andconcentrated. The concentrate was purified by reverse phaseHPLC (ZorbaxSB, C-18, 30% to 100% acetonitrile/water/0.1% trifluoroacetic acid).

Example 3C 3-(3-(3-chlorophenoxy)propyl)-1H-indole-2-carboxylic acid

A mixture of EXAMPLE 3B (0.035 mg) and LiOH (0.1 g) in methanol/water(1:1, 5 mL) was heated at 150° C. under microwave (CEM Discover)conditions (70 W) for 10 minutes. The reaction mixture was concentrated,diluted with water (2 mL), treated with 5 MHCl, and extracted with ethylacetate. The extract was dried (Na₂SO₄), filtered and concentrated. Theconcentrate was purified by reverse phaseHPLC (Zorbax SB, C-18, 20% to100% acetonitrile/water/0.1% trifluoroacetic acid). ¹H NMR (400 MHz,DMSO-d₆) δ 12.88 (brs, 1H), 11.40 (s, 1H), 7.63 (d, 1H), 7.39 (d, 1H),7.24 (m, 2H), 6.92 (m, 4H), 3.97 (t, 2H), 3.20 (t, 2H), 2.05 (m, 2H).

Example 4A ethyl3-(3-(3-(trifluoromethyl)phenoxy)propyl)-1H-indole-2-carboxylate

This example was prepared by replacing 3-(trifluoromethyl)phenol for3-chlorophenol in EXAMPLE 3B.

Example 4B3-(3-(3-(trifluoromethyl)phenoxy)propyl)-1H-indole-2-carboxylic acid

This example was prepared by replacing EXAMPLE 4A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (brs, 1H), 11.40 (s, 1H),7.63 (d, 1H), 7.49 (t, 1H), 7.39 (d, 1H), 7.22 (m, 4H), 6.98 (t, 1H),4.04 (t, 2H), 3.21 (t, 2H), 2.07 (m, 2H).

Example 5A ethyl3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by replacing 1-naphthol for 3-chlorophenol inEXAMPLE 3B.

Example 5B 3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 5A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, DMSO-d₆) δ 12.96 (brs, 1H), 11.44 (s, 1H),8.24 (d, 1H), 7.86 (d, 1H), 7.66 (d, 1H), 7.52 (m, 2H), 7.41 (m, 3H),7.21 (t, 1H), 6.96 (t, 1H), 6.87 (d, 1H), 4.16 (t, 2H), 3.33 (m, 2H),2.20 (m, 2H).

Example 6A ethyl 3-(3-(2-benzylphenoxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting 2-benzylphenol for3-chlorophenol in EXAMPLE 3B.

Example 6B 3-(3-(2-benzylphenoxy)propyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 6A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, DMSO-d₆) δ 12.92 (brs, 1H), 11.40 (s, 1H),7.50 (d, 1H), 7.38 (d, 1H), 7.22 (m, 5H), 7.13 (m, 3H), 6.95 (t, 1H),6.85 (m, 2H), 3.95 (m, 4H), 3.18 (t, 2H), 2.04 (m, 2H).

Example 7A ethyl3-(3-(2,3-dihydro-1H-inden-5-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting 2,3-dihydro-1H-inden-5-ol for3-chlorophenol in EXAMPLE 3B.

Example 7B3-(3-(2,3-dihydro-1H-inden-5-yloxy)propyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 7A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, DMSO-d₆) δ 12.90 (brs, 1H), 11.41 (s, 1H),7.63 (d, 1H), 7.39 (d, 1H), 7.21 (t, 1H), 7.07 (d, 1H), 7.00 (t, 1H),6.74 (s, 1H), 6.64 (dd, 1H), 3.90 (t, 2H), 3.19 (t, 2H), 2.77 (m, 4H),2.00 (m, 4H).

Example 8A ethyl3-(3-(3-methylnaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting 3-methylnaphthalen-1-ol for3-chlorophenol in EXAMPLE 3B.

Example 8B3-(3-(3-methylnaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 8A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, DMSO-d₆) δ 12.91 (brs, 1H), 11.43 (s, 1H),8.00 (d, 1H), 7.86 (d, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.44 (m, 3H),7.34 (d, 1H), 7.24 (t, 1H), 7.05 (t, 1H), 3.97 (t, 2H), 2.37 (s, 3H),2.21 (m, 2H).

Example 9A ethyl3-(3-(2-methylnaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting 2-methylnaphthalen-1-ol for3-chlorophenol in EXAMPLE 3B.

Example 9B 3-(3-((2-methyl-1-naphthyl)oxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 9A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, DMSO-d₆) δ 12.89 (br. s, 1H), 11.4 (s, 1H),8.00 (d, 1H), 7.86 (d, 1H), 7.70 (d, 1H), 7.59 (d, 1H), 7.45 (m, 3H),7.34 (d, 1H), 7.5 (m, 1H), 7.05 (t, 1H), 3.97 (t, 2H), 2.37 (s, 3H),2.15-2.26 (m, 2H).

Example 10A ethyl3-(3-(methylsulfonyloxy)propyl)-1H-indole-2-carboxylate

To a mixture of EXAMPLE 3A (0.125 g) and triethylamine (0.21 mL) inacetonitrile (3 mL) at 0-5° C. was added methanesulfonyl chloride(0.0404 mL). After 30 minutes, the mixture was concentrated, and theconcentrate was purified by flash chromatography on silica gel with0-30% ethyl acetate/hexanes.

Example 10B ethyl3-(3-(naphthalen-1-ylthio)propyl)-1H-indole-2-carboxylate

A mixture of EXAMPLE 10A (42 mg), naphthalene thiol (45 mg), andpotassium carbonate (36 mg) in acetonitrile (2 mL) was heated at 80° C.for 3 days. The reaction mixture was poured into water, extracted withdichloromethane and purified by flash chromatography on silica gel with0-20% ethyl acetate in hexanes.

Example 10C 3-(3-(1-naphthylthio)propyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 10B for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (300 MHz, DMSO-d₆) δ 12.92 (s, 1H), 11.42 (s, 1H),8.11-8.32 (m, 1H), 7.85-8.03 (m, 1H), 7.77 (d, 1H), 7.50-7.67 (m, 2H),7.32-7.50 (m, 2H), 7.21 (t, 1H), 6.98 (t, 1H), 3.12-3.26 (m, 2H), 3.06(t, 2H), 1.85-2.05 (m, 2H).

Example 11A ethyl5-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate

To a mixture of 4-bromoaniline (3.44 g) in 5M aqueous HCl (12 mL) at 0°C. was added 2.5M NaNO₂ (1.38 g) in water (20 mL). After the addition,4.5M sodium acetate (9.23 g) in water (25 mL) was added, followed by2-oxo-cyclopentanecarboxylic acid ethyl ester (3 mL). The mixture wasstirred at 0° C. for 15 minutes, warmed to 19° C. over two hours, andextracted with dichloromethane. The extract was dried (MgSO₄), filteredand concentrated. The concentrate was dissolved in 10% H₂SO₄ in ethanol(22 mL) and refluxed overnight, cooled to room temperature, quenchedwith water (0.4 L), and filtered.

Example 11B ethyl 5-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 11A for ethyl3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate in EXAMPLE 3A.

Example 11C ethyl5-bromo-(3-(3-(naphthalen-1-yloxy)propyl))-1H-indole-2-carboxylate

This example was prepared by substituting 1-naphthol for 3-chlorophenoland EXAMPLE 11B for EXAMPLE 3A in EXAMPLE 3B.

Example 11D5-bromo-(3-(3-(naphthalen-1-yloxy)propyl))-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 11C for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (brs, 1H), 11.63 (s, 1H),8.23 (m, 1H), 7.85 (m, 2H), 7.49 (m, 3H), 7.33 (m, 3H), 6.86 (d, 1H),4.15 (t, 2H), 2.19 (m, 2H).

Example 123-(3-(1-naphthyloxy)propyl)-5-((1E)-3-phenylprop-1-enyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 11C (45.2 mg), (E)-3-phenylprop-1-enylboronic acid(21.1 mg), bis(triphenylphosphine)palladium(II) dichloride (catalytic),and 2M LiOH (0.3 mL) in 7/2/3 dimethoxyethane/ethanol/H₂O (2 mL) washeated under microwave (CEM Discover) conditions at 150° C. for 30minutes. The mixture was quenched with 1 MHCl (0.4 mL) and extractedwith ethyl acetate. The extract was dried (MgSO₄), filtered, andconcentrated. The cruconcentrate was purified by reverse phaseHPLC(Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid).¹H NMR (500 MHz, DMSO-d₆) δ 12.95 (brs, 1H), 11.44 (s, 1H), 8.34 (d,1H), 7.88 (d, 1H), 7.54 (m, 2H), 7.44 (m, 2H), 7.31 (m, 5H), 7.18 (m,3H), 6.83 (d, 1H), 6.00 (m, 2H), 4.08 (t, 2H), 2.21 (m, 2H).

Example 135-((E)-2-cyclohexylvinyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-2-cyclohexylvinylboronicacid for (E)-3-phenylprop-1-enylboronic acid in EXAMPLE 12. ¹H NMR (500MHz, DMSO-d₆) δ 12.95 (brs, 1H), 11.42 (s, 1H), 8.36 (m, 1H), 7.88 (m,1H), 7.56 (m, 2H), 7.43 (m, 2H), 7.34 (m, 1H), 7.26 (m, 2H), 6.81 (d,1H), 5.80 (m, 2H), 4.07 (t, 2H), 2.21 (t, 2H), 1.85 (m, 1H), 1.62 (m,5H), 1.20 (m, 3H), 0.92 (m, 2H).

Example 143-(3-(1-naphthyloxy)propyl)-5-((E)-2-phenylvinyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid for(E)-3-phenylprop-1-enylboronic acid in EXAMPLE 12. ¹H NMR (400 MHz,DMSO-d₆) δ 13.03 (br. s, 1H), 11.56 (s, 1H), 8.39 (m, 1H), 7.92 (m, 1H),7.58 (m, 4H), 7.43 (d, 1H), 7.28 (m, 7H), 6.92 (d, 1H), 6.84 (d, 1H),6.68 (d, 1H), 4.10 (t, 2H), 3.39 (t, 2H), 2.25 (m, 2H).

Example 155-(4-fluorophenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting 4-fluoro-phenylboronic acidfor (E)-3-phenylprop-1-enylboronic acid in EXAMPLE 12. ¹H NMR (500 MHz,DMSO-d₆) δ 13.05 (brs, 1H), 11.56 (s, 1H), 8.33 (d, 1H), 7.92 (d, 1H),7.71 (s, 1H), 7.50 (m, 5H), 7.35 (t, 1H), 7.20 (m, 2H), 6.96 (m, 2H),6.85 (d, 1H), 4.11 (t, 2H), 3.40 (t, 2H), 2.25 (m, 2H).

Example 163-(3-(1-naphthyloxy)propyl)-5-(2-phenylethyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 14 (0.005 g), cyclohexene (0.5 mL), Pd/C(catalytic) in ethanol (4 mL) was heated at 130° C. (270 W) in amicrowave (CEM Discover) for 10 minutes. The reaction mixture wasfiltered and the filtrate was concentrated. The concentrate was purifiedby preparative reverse phaseHPLC (Zorbax SB, C-18, 20% to 100%acetonitrile/water/0.1% trifluoroacetic acid) to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ 12.88 (brs, 1H), 11.32 (s, 1H),8.34 (m, 1H), 7.84 (m, 1H), 7.53 (m, 2H), 7.42 (d, 1H), 7.34 (m, 2H),7.23 (m, 3H), 7.13 (m, 1H), 7.01 (m, 3H), 6.84 (d, 1H), 4.08 (t, 2H),2.56 (s, 4H), 2.19 (m, 2H).

Example 173-(3-((7-methyl-2,3-dihydro-1H-inden-4-yl)oxy)propyl)-1H-indole-2-carboxylicacid Example 17A

This example was prepared by substituting7-methyl-2,3-dihydro-1H-inden-4-ol for 3-chlorophenol in EXAMPLE 3B.

Example 17B3-(3-((7-methyl-2,3-dihydro-1H-inden-4-yl)oxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 17A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.72 (s, 1H), 7.73 (d, 1H),7.36 (m, 2H), 7.14 (t, 1H), 6.87 (d, 1H), 6.55 (d, 1H), 4.03 (t, 2H),3.34 (t, 2H), 2.95 (t, 2H), 2.84 (t, 2H), 2.19 (m, 5H), 2.09 (m, 2H).

Example 18A ethyl3-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting5,6,7,8-tetrahydronaphthalen-1-ol for 3-chlorophenol in EXAMPLE 3B.

Example 18B3-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 18A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.75 (s, 1H), 7.73 (d, 1H),7.38 (m, 2H), 7.14 (t, 1H), 7.01 (t, 1H), 6.68 (d, 1H), 6.60 (d, 1H),4.03 (t, 2H), 3.37 (t, 2H), 2.76 (m, 4H), 2.22 (m, 2H), 1.80 (m, 4H).

Example 19A ethyl4-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate

This example was prepared by substituting 3-bromoaniline for4-bromoaniline in EXAMPLE 11A.

Example 19B ethyl 4-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 19A for ethyl3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate in EXAMPLE 3A.

Example 19C ethyl4-bromo-(3-(3-(naphthalen-1-yloxy)propyl))-1H-indole-2-carboxylate

This example was prepared by substituting 1-naphthol for 3-chlorophenoland EXAMPLE 19B for EXAMPLE 3A in EXAMPLE 3B.

Example 19D4-(4-fluorophenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting 4-fluoro-phenylboronic acidfor (E)-3-phenylprop-1-enylboronic acid and EXAMPLE 19C for EXAMPLE 11Cin EXAMPLE 12. ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.76 (s, 1H), 7.73 (d,1H), 7.38 (m, 2H), 7.14 (t, 1H), 7.02 (t, 1H), 6.68 (d, 1H), 6.59 (d,1H), 4.02 (t, 2H), 3.37 (t, 2H), 2.75 (m, 4H), 2.22 (m, 2H), 1.80 (m,4H).

Example 20A ethyl6-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate

This example was prepared by substituting 3-bromoaniline for4-bromoaniline in EXAMPLE 11A.

Example 20B ethyl 6-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 20A for ethyl3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate in EXAMPLE 3A.

Example 20C ethyl6-bromo-(3-(3-(naphthalen-1-yloxy)propyl))-1H-indole-2-carboxylate

This example was prepared by substituting 1-naphthol for 3-chlorophenoland EXAMPLE 20B for EXAMPLE 3A in EXAMPLE 3B.

Example 20D3-(3-(1-naphthyloxy)propyl)-6-((E)-2-phenylvinyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid for(E)-3-phenylprop-1-enylboronic acid and EXAMPLE 20C for EXAMPLE 11C inEXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 12.98 (brs, 1H), 11.53 (s, 1H),8.24 (m, 1H), 7.86 (m, 1H), 7.64 (m, 3H), 7.53 (m, 3H), 7.45 (m, 1H),7.36 (m, 5H), 7.21 (m, 2H), 6.88 (d, 1H), 4.17 (t, 2H), 2.21 (m, 2H).

Example 213-(3-(1-naphthyloxy)propyl)-6-((1E)-3-phenylprop-1-enyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 20C for EXAMPLE 11C inEXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 12.94 (brs, 1H), 11.39 (s, 1H),8.21 (d, 1H), 7.86 (d, 1H), 7.54 (m, 3H), 7.44 (m, 1H), 7.32 (m, 6H),7.21 (m, 1H), 7.12 (d, 1H), 6.87 (d, 1H), 6.55 (d, 1H), 6.37 (m, 1H),4.14 (t, 2H), 3.54 (d, 2H), 2.19 (m, 2H).

Example 22 3-(3-(1-naphthyloxy)propyl)-4-((1E)-3-phenylprop-1-enyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 19C for EXAMPLE 11C inEXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 13.01 (brs, 1H), 11.49 (s, 1H),8.19 (m, 1H), 7.81 (m, 1H), 7.33 (m, 13H), 6.91 (d, 1H), 6.32 (m, 1H),4.14 (t, 2H), 3.55 (m, 2H), 3.45 (m, 2H), 2.12 (m, 2H).

Example 236-(3-(benzyloxy)phenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting 3-(benzyloxy)-phenylboronicacid for (E)-3-phenylprop-1-enylboronic acid and EXAMPLE 20C for EXAMPLE11C in EXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 13.03 (s, 1H), 11.52 (s,1H), 8.24 (m, 1H), 7.86 (s, 1H), 7.73 (d, 1H), 7.60 (s, 1H), 7.35 (m,13H), 7.01 (m, 1H), 6.88 (d, 1H), 5.18 (s, 2H), 4.18 (t, 2H), 2.24 (m,2H).

Example 244-(3-(benzyloxy)phenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting 3-(benzyloxy)-phenylboronicacid for (E)-3-phenylprop-1-enylboronic acid and EXAMPLE 19C for EXAMPLE11C in EXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 12.98 (brs, 1H), 11.62(s, 1H), 8.03 (d, 1H), 7.83 (d, 1H), 7.47 (m, 4H), 7.34 (m, 4H), 7.24(m, 4H), 7.03 (m, 3H), 6.83 (d, 1H), 6.70 (d, 1H), 5.07 (s, 2H), 3.65(m, 2H), 2.84 (m, 2H), 1.72 (m, 2H).

Example 25A ethyl5-bromo-3-(4-ethoxy-4-oxobutyl)-1H-indole-2-carboxylate

This example was prepared by substituting ethyl2-oxocyclohexanecarboxylate for ethyl 2-oxocyclopentanecarboxylate inEXAMPLE 11A.

Example 25B ethyl 5-bromo-3-(4-hydroxybutyl)-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 25A for ethyl3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate in EXAMPLE 3A.

Example 25C ethyl5-bromo-3-(4-(naphthalen-1-yloxy)butyl)-1H-indole-2-carboxylate

This example was prepared by substituting 1-naphthol for 3-chlorophenoland EXAMPLE 25B for EXAMPLE 3A in EXAMPLE 3B.

Example 25D 5-bromo-3-(4-(1-naphthyloxy)butyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 25C for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, DMSO-d₆) δ 13.11 (brs, 1H), 11.61 (s, 1H),8.09 (d, 1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.47 (m, 3H), 7.36 (m, 3H),6.93 (d, 1H), 4.16 (m, 2H), 3.16 (m, 2H), 1.88 (m, 4H).

Example 26A ethyl1-methyl-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

To a mixture of 60% oily NaH (20 mg) in DMF (5 mL) was added EXAMPLE 5A(0.1 g). After stirring at room temperature for 30 minutes, CH₃I (0.1mL) was added, and the mixture was stirred for 16 hours. Water anddichloromethane were added to the mixture, and the extract was separatedand concentrated.

Example 26B 1-methyl-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 26A for EXAMPLE 3B inEXAMPLE 3C. ¹H NMR (500 MHz, DMSO-d₆) δ 13.12 (brs, 1H), 8.20 (d, 1H),7.86 (d, 1H), 7.69 (d, 1H), 7.52 (m, 3H), 7.44 (d, 1H), 7.37 (t, 1H),7.30 (t, 1H), 7.00 (t, 1H), 6.87 (d, 1H), 4.15 (t, 2H), 3.96 (s, 3H),2.19 (m, 2H).

Example 27 3-(3-(1-naphthyloxy)propyl)-6-phenyl-1H-indole-2-carboxylicacid

This example was prepared by substituting phenylboronic acid for(E)-3-phenylprop-1-enylboronic acid and EXAMPLE 20C for EXAMPLE 11C inEXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 13.00 (brs, 1H), 11.65 (s, 1H),8.01 (d, 1H), 7.83 (d, 1H), 7.43 (m, 10H), 7.28 (m, 1H), 6.83 (d, 1H),6.70 (d, 1H), 3.65 (t, 2H), 2.88 (m, 2H), 1.67 (m, 2H).

Example 286-(2-methylphenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting 2-methylphenylboronic acid for(E)-3-phenylprop-1-enylboronic acid and EXAMPLE 20C for EXAMPLE 11C inEXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 12.97 (brs, 1H), 11.62 (s, 1H),8.03 (d, 1H), 7.83 (d, 1H), 7.37 (m, 10H), 6.72 (m, 2H), 3.60 (m, 2H),2.91 (m, 1H), 2.42 (m, 1H), 1.99 (s, 3H), 1.66 (m, 2H).

Example 296-(3-methylphenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting 3-methylphenylboronic acid for(E)-3-phenylprop-1-enylboronic acid and EXAMPLE 20C for EXAMPLE 11C inEXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 12.99 (brs, 1H), 11.64 (s, 1H),8.01 (d, 1H), 7.83 (d, 1H), 7.35 (m, 10H), 6.82 (d, 1H), 6.72 (d, 1H),3.67 (m, 2H), 2.85 (m, 2H), 2.30 (s, 3H), 1.74 (m, 2H).

Example 306-(4-methylphenyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting 4-methylphenylboronic acid for(E)-3-phenylprop-1-enylboronic acid and EXAMPLE 20C for EXAMPLE 11C inEXAMPLE 12. ¹H NMR (500 MHz, DMSO-d₆) δ 12.98 (s, 1H), 11.61 (s, 1H),8.00 (d, 1H), 7.83 (d, 1H), 7.36 (m, 10H), 6.80 (d, 1H), 6.70 (d, 1H),3.63 (t, 2H), 2.90 (m, 2H), 2.29 (s, 3H), 1.69 (m, 2H).

Example 31A 1-(3-bromopropoxy)naphthalene

A mixture of 1-naphthol (3.45 g), 3-bromopropanol (1.75 mL),di-t-butyl-azo-dicarboxylate (5.52 g) and triphenylphosphine (6.28 g) inTHF (30 mL) was stirred at room temperature for 16 hours andconcentrated. The concentrate was diluted with ethyl acetate, washedwith water and brine and dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by silica gel chromatography with 0-7% ethylacetate/hexane.

Example 31B ethyl 3-bromo-1H-indole-2-carboxylate

A mixture of ethyl-2-indole carboxylate (1.89 g) and N-bromosuccinimide(1.77 g) in THF (30 mL) was stirred at room temperature for 1 hour. Themixture was poured into water (150 mL) and filtered. The filtrate waswashed with THF, dried under vacuum at 60° C., and recrystallized fromethyl acetate/hexanes.

Example 31C ethyl3-bromo-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

EXAMPLE 31B (0.58 g) was added to a mixture of NaH (0.112 g) in DMF (5mL). The mixture was stirred for 30 minutes, treated with EXAMPLE 31A(0.532 g) in DMF (3 mL), stirred at 80° C. for 1 hour, quenched withsaturated NH₄Cl, and extracted with ethyl acetate. The extract waswashed with water, and brine and dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by silica gel chromatographywith 0-7% ethyl acetate/hexanes.

Example 31D ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-ortho-tolyl-1H-indole-2-carboxylate

A mixture of EXAMPLE 31C (90 mg), ortho-tolboronic acid (54 mg),tris(dibenzylideneacetone)dipalladium(0) (18 mg),tri-tert-butylphosphine tetrafluoroborate (5.8 mg), CsF (90 mg) in THF(2 mL) was stirred at room temperature for 16 hours, diluted with ethylacetate and was washed with water and brine. The combine extract wasdried (MgSO₄), filtered, and concentrated.

Example 31E3-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 31D in 1N LiOH:dioxane (0.5 mL: 2 mL) was heatedunder microwave conditions (CEM Discover) at 130° C. for 30 minutes. Themixture was quenched with 1NHCl aqueous mixture (0.5 mL) and extractedwith ethyl acetate. The extract was dried (Na₂SO₄), filtered, andconcentrated. The concentrate was purified by reverse phaseHPLC (ZorbaxSB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). ¹H NMR(400 MHz, DMSO-d₆) δ 12.73 (bs, 1H), 8.23 (d, 1H), 7.87 (d, 1H), 7.66(d, 1H), 7.52 (m, 3H), 7.38 (t, 1H), 7.26 (m, 4H), 7.12 (m, 2H), 7.04(m, 1H), 6.87 (d, 2H), 4.91 (t, 2H), 4.19 (t, 2H), 2.38 (m, 2H), 2.01(s, 3H).

Example 32A ethyl3-(naphthalen-1-yl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with1-naphthaleneboronic acid in EXAMPLE 31D.

Example 32B3-(1-naphthyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 32Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (bs, 1H), 8.22 (d,1H), 7.96 (m, 2H), 7.87 (d, 1H), 7.74 (d, 1H), 7.48 (m, 8H), 7.31 (m,1H), 7.25 (m, 1H), 7.02 (m, 2H), 6.91 (d, 1H), 4.98 (t, 2H), 4.25 (t,2H), 2.45 (m, 2H).

Example 33A ethyl3-(3-(3-(dimethylamino)propylcarbamoyl)phenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid withN-(3-(N′,N′-dimethylamino)propyl)benzamide-3-boronic acid pinacol esterin EXAMPLE 31D.

Example 33B3-(3-(((3-(dimethylamino)propyl)amino)carbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 33Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (bs, 1H), 8.64 (t,1H), 8.25 (d, 1H), 7.93 (s, 1H), 7.86 (m, 2H), 7.70 (d, 1H), 7.53 (m,5H), 7.39 (m, 2H), 7.27 (m, 1H), 7.11 (m, 1H), 6.89 (d, 1H), 4.89 (t,2H), 4.20 (t, 2H), 3.10 (t, 2H), 2.78 (s, 6H), 2.38 (m, 2H), 1.88 (m,2H).

Example 34A ethyl3-(biphenyl-2-yl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with2-biphenylboronic acid in EXAMPLE 31D.

Example 34B3-(1,1′-biphenyl-2-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 34Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (br, 1H), 8.24 (d,1H), 7.86 (d, 1H), 7.52 (m, 3H), 7.38 (m, 6H), 7.08 (m, 7H), 6.93 (m,1H), 6.76 (d, 1H), 4.78 (m, 2H), 4.00 (m, 2H), 2.22 (m, 2H).

Example 35A 2-(3-bromopropoxy)naphthalene

This example was prepared by substituting 1-naphthol with 2-naphthol inEXAMPLE 31A.

Example 35B ethyl3-bromo-1-(3-(naphthalen-2-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with EXAMPLE 35Ain EXAMPLE 31C.

Example 35C ethyl1-(3-(naphthalen-2-yloxy)propyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31C with EXAMPLE 35Bin EXAMPLE 31D.

Example 35D3-(2-methylphenyl)-1-(3-(2-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 35Cin EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br, 1H), 7.82 (m,2H), 7.73 (d, 1H), 7.66 (d, 1H), 7.44 (m, 1H), 7.33 (m, 1H), 7.21 (m,7H), 7.09 (m, 1H), 7.04 (m, 1H), 4.84 (t, 2H), 4.07 (t, 2H), 2.30 (m2H), 2.01 (s, 3H).

Example 36A 5-(3-bromopropoxy)-1,2,3,4-tetrahydronaphthalene

This example was prepared by substituting 1-naphthol with5,6,7,8-tetrahydro-1-naphthol in EXAMPLE 31A.

Example 36B ethyl3-bromo-1-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with EXAMPLE 36Ain EXAMPLE 31C.

Example 36C ethyl1-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31C with EXAMPLE 36Bin EXAMPLE 31D.

Example 36D3-(2-methylphenyl)-1-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 36Cin EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br, 1H), 7.62 (d,1H), 7.29 (m, 4H), 7.09 (m, 3H), 6.98 (m, 1H), 6.64 (m, 2H), 4.79 (t,2H), 3.96 (t, 2H), 2.68 (m 2H), 2.61 (t, 2H), 2.23 (m, 2H), 2.02 (s,3H), 1.71 (m, 4H).

Example 37A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-m-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid withm-tolylboronic acid in EXAMPLE 31D.

Example 37B3-(3-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 37Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (br, 1H), 8.21 (d,1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.50 (m, 4H), 7.38 (m, 1H), 7.31 (m,1H), 7.24 (m, 1H), 7.19 (s, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 6.88 (d,1H), 4.85 (t, 2H), 4.19 (t, 2H), 2.37 (m, 2H), 2.35 (s, 3H).

Example 38A ethyl3-(3-chlorophenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with3-chlorophenylboronic acid in EXAMPLE 31D.

Example 38B3-(3-chlorophenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 38Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br, 1H), 8.17 (d,1H), 7.87 (d, 1H), 7.69 (d, 1H), 7.45 (m, 8H), 7.25 (m, 2H), 7.12 (m,1H), 6.88 (d, 1H), 4.88 (t, 2H), 4.20 (t, 2H), 2.38 (m, 2H).

Example 39A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-phenyl-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid withphenylboronic acid in EXAMPLE 31D.

Example 39B 1-(3-(1-naphthyloxy)propyl)-3-phenyl-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 39Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (br, 1H), 8.24 (d,1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.52 (m, 2H), 7.40 (m, 7H), 7.24 (m,2H), 7.09 (m, 1H), 6.88 (d, 1H), 4.86 (t, 2H), 4.20 (t, 2H), 2.37 (m,2H).

Example 40A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with2-(trifluoromethyl)phenylboronic acid in EXAMPLE 31D.

Example 40B1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 40Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (br, 1H), 8.24 (d,1H), 7.87 (d, 1H), 7.82 (d, 1H), 7.69 (m, 2H), 7.60 (m, 1H), 7.52 (m,3H), 7.36 (m, 2H), 7.24 (m, 1H), 7.06 (m, 2H), 6.88 (d, 1H), 4.92 (t,2H), 4.17 (t, 2H), 2.36 (m, 2H).

Example 41A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with3-(trifluoromethyl)phenylboronic acid in EXAMPLE 31D.

Example 41B1-(3-(1-naphthyloxy)propyl)-3-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 41Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (br, 1H), 8.16 (d,1H), 7.87 (d, 1H), 7.70 (m, 5H), 7.48 (m, 3H), 7.38 (m, 2H), 7.28 (m,1H), 7.13 (m, 1H), 6.88 (d, 1H), 4.90 (t, 2H), 4.21 (t, 2H), 2.39 (m,2H).

Example 42A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with4-(trifluoromethyl)phenylboronic acid in EXAMPLE 31D.

Example 42B1-(3-(1-naphthyloxy)propyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 42Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (br, 1H), 8.21 (d,1H), 7.87 (d, 1H), 7.78 (d, 2H), 7.70 (d, 1H), 7.63 (d, 2H), 7.50 (m,4H), 7.39 (m, 1H), 7.27 (m, 1H), 7.13 (m, 1H), 6.88 (d, 1H), 4.90 (t,2H), 4.21 (t, 2H), 2.39 (m, 2H).

Example 43A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with4-(trifluoromethoxyphenylboronic acid in EXAMPLE 31D.

Example 43B1-(3-(1-naphthyloxy)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 43Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (br, 1H), 8.22 (d,1H), 7.87 (d, 1H), 7.70 (m, 5H), 7.53 (m, 4H), 7.43 (m, 5H), 7.26 (m,1H), 7.13 (m, 1H), 6.88 (d, 1H), 4.88 (t, 2H), 4.21 (t, 2H), 2.38 (m,2H).

Example 44A ethyl3-(2,3-dimethylphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with2,3-dimethylphenylboronic acid in EXAMPLE 31D.

Example 44B3-(2,3-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 44Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.67 (br, 1H), 8.24 (d,1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.53 (m, 3H), 7.38 (m, 1H), 7.23 (m,1H), 7.15 (m, 1H), 7.10 (m, 2H), 7.03 (m, 1H), 6.99 (d, 1H), 6.88 (d,1H), 4.90 (t, 2H), 4.19 (t, 2H), 2.38 (m, 2H), 2.29 (s, 3H), 1.93 (s,3H).

Example 45A ethyl3-(2,5-dimethylphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with2,5-dimethylphenylboronic acid in EXAMPLE 31D.

Example 45B3-(2,5-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 45Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br, 1H), 8.19 (d,1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.49 (m, 3H), 7.38 (m, 1H), 7.23 (m,1H), 7.15 (m, 1H), 7.07 (m, 3H), 6.93 (d, 1H), 6.88 (d, 1H), 4.90 (t,2H), 4.19 (t, 2H), 2.38 (m, 2H), 2.27 (s, 3H), 1.96 (s, 3H).

Example 46A ethyl3-(3,4-dimethylphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with3,4-dimethylphenylboronic acid in EXAMPLE 31D.

Example 46B3-(3,4-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 46Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (br, 1H), 8.22 (d,1H), 7.87 (d, 1H), 7.64 (d, 1H), 7.45 (m, 5H), 7.22 (m, 1H), 7.17 (m,2H), 7.07 (m, 2H), 6.88 (d, 1H), 4.84 (t, 2H), 4.19 (t, 2H), 2.36 (m,2H), 2.27 (s, 3H), 2.25 (s, 3H).

Example 47A ethyl3-(3,5-dimethylphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with3,5-dimethylphenylboronic acid in EXAMPLE 31D.

Example 47B3-(3,5-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 47Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.92 (br, 1H), 8.19 (d,1H), 7.87 (d, 1H), 7.64 (d, 1H), 7.48 (m, 5H), 7.23 (m, 1H), 7.08 (m,1H), 6.97 (s, 3H), 6.87 (d, 1H), 4.84 (t, 2H), 4.19 (t, 2H), 2.36 (m,2H), 2.31 (s, 3H).

Example 48A ethyl3-(2,5-dimethoxyphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with2,5-dimethoxyphenylboronic acid in EXAMPLE 31D.

Example 48B3-(2,5-dimethoxyphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 48Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.73 (br, 1H), 8.26 (m,1H), 7.88 (m, 1H), 7.64 (d, 1H), 7.53 (m, 3H), 7.35 (m, 2H), 7.22 (m,1H), 7.08 (m, 1H), 6.97 (d, 1H), 6.89 (m, 2H), 6.83 (d, 1H), 4.84 (t,2H), 4.19 (t, 2H), 3.72 (s, 3H), 3.60 (s, 3H), 2.35 (m, 2H).

Example 49A ethyl3-(3,4-dimethoxyphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting ortho-tolylboronic acid with3,4-dimethoxyphenylboronic acid in EXAMPLE 31D.

Example 49B3-(3,4-dimethoxyphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 49Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (br, 1H), 8.23 (m,1H), 7.88 (m, 1H), 7.64 (d, 1H), 7.50 (m, 4H), 7.38 (m, 1H), 7.23 (m,1H), 7.08 (m, 1H), 7.02 (d, 1H), 6.97 (d, 1H), 6.94 (dd, 1H), 6.88 (d,1H), 4.84 (t, 2H), 4.19 (t, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 2.35 (m,2H).

Example 50A 1-(4-bromobutoxy)naphthalene

This example was prepared by substituting 3-bromopropanol with4-bromobutanol in EXAMPLE 31A.

Example 50B ethyl 3-ortho-tolyl-1H-indole-2-carboxylate

A mixture of EXAMPLE 31B (1.08 g), ortho-tolylboronic acid (1.1 g),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (140 mg) indimethoxyethane:2N aqueous Na₂CO₃ (25 mL:5 mL) was stirred undernitrogen at 80° C. for 16 hours, diluted with ethyl acetate and waswashed with water and brine. The organic phase was dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flashchromatography on silica gel with 0-10% ethyl acetate/hexanes.

Example 50C ethyl1-(4-(naphthalen-1-yloxy)butyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with EXAMPLE 50Aand substituting EXAMPLE 31B with EXAMPLE 50B in EXAMPLE 31C.

Example 50D3-(2-methylphenyl)-1-(4-(1-naphthyloxy)butyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 50Cin EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br, 1H), 8.09 (d,1H), 7.85 (d, 1H), 7.64 (d, 1H), 7.47 (m, 3H), 7.38 (m, 1H), 7.26 (m,4H), 7.16 (m, 1H), 7.09 (m, 2H), 6.91 (d, 1H), 4.75 (t, 2H), 4.16 (t,2H), 2.02 (m, 5H), 1.86 (m, 2H).

Example 51A 2-(4-bromobutoxy)naphthalene

This example was prepared by substituting 3-bromopropanol with4-bromobutanol and substituting 1-naphthol with 2-naphthol in EXAMPLE31A.

Example 51B ethyl1-(4-(naphthalen-2-yloxy)butyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with EXAMPLE 51Aand substituting EXAMPLE 31B with EXAMPLE 50B in EXAMPLE 31C.

Example 51C3-(2-methylphenyl)-1-(4-(2-naphthyloxy)butyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 51Bin EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br, 1H), 7.79 (m,3H), 7.69 (d, 1H), 7.44 (m, 1H), 7.32 (m, 5H), 7.21 (m, 1H), 7.11 (m,4H), 4.72 (t, 2H), 4.10 (t, 2H), 2.02 (s, 3H), 1.96 (m, 2H), 1.80 (m,2H).

Example 52A 1-(4-bromobutoxy)-2,3-dichlorobenzene

This example was prepared by substituting 3-bromopropanol with4-bromobutanol and substituting 1-naphthol with 2,3-dichlorophenol inEXAMPLE 31A.

Example 52B ethyl1-(4-(2,3-dichlorophenoxy)butyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with EXAMPLE 52Aand substituting EXAMPLE 31B with EXAMPLE 50B in EXAMPLE 31C.

Example 52C1-(4-(2,3-dichlorophenoxy)butyl)-3-(2-methylphenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 52Bin EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.66 (br, 1H), 7.67 (d,1H), 7.34 (m, 1H), 7.26 (m, 4H), 7.18 (dd, 1H), 7.14 (m, 1H), 7.08 (m,3H), 4.71 (t, 2H), 4.10 (t, 2H), 2.01 (s, 3H), 1.95 (m, 2H), 1.76 (m,2H).

Example 53A ethyl1-(2-(2,4-dichlorophenoxy)ethyl)-3-o-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with1-(2-bromoethoxy)-2,4-dichlorobenzene and substituting EXAMPLE 31B withEXAMPLE 50B in EXAMPLE 31C.

Example 53B1-(2-(2,4-dichlorophenoxy)ethyl)-3-(2-methylphenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 53Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (br, 1H), 7.75 (d,1H), 7.49 (d, 1H), 7.35 (m, 1H), 7.28 (m, 3H), 7.22 (m, 1H), 7.14 (m,2H), 7.07 (d, 2H), 5.07 (t, 2H), 4.45 (t, 2H), 2.01 (s, 3H).

Example 54A ethyl1-(3-(2,4-dichlorophenoxy)propyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with1-(3-bromopropoxy)-2,4-dichlorobenzene and EXAMPLE 31B with EXAMPLE 50Bin EXAMPLE 31C.

Example 54B1-(3-(2,4-dichlorophenoxy)propyl)-3-(2-methylphenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 54Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (br, 1H), 7.64 (d,1H), 7.59 (d, 1H), 7.35 (dd, 1H), 7.26 (m, 4H), 7.15 (m, 1H), 7.06 (m,3H), 4.78 (t, 2H), 4.05 (t, 2H), 2.27 (m, 2H), 2.01 (s, 3H).

Example 551-(4-(2,4-dichlorophenoxy)butyl)-3-(2-methylphenyl)-1H-indole-2-carboxylicacid Example 55A ethyl1-(4-(2,4-dichlorophenoxy)butyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with1-(4-bromobutyoxy)-2,4-dichlorobenzene and substituting EXAMPLE 31B withEXAMPLE 50B in EXAMPLE 31C.

Example 55B1-(4-(2,4-dichlorophenoxy)butyl)-3-(2-methylphenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 55Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (br, 1H), 7.64 (d,1H), 7.54 (d, 1H), 7.33 (m, 2H), 7.24 (m, 3H), 7.11 (m, 4H), 4.70 (t,2H), 4.07 (t, 2H), 2.01 (s, 3H), 1.94 (m, 2H), 1.74 (m, 2H).

Example 56A ethyl3-benzyl-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

A mixture of EXAMPLE 31C (100 mg), 0.5M benzyl zinc(II) bromide in THF(1.32 mL) and(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (18 mg) inTHF (2 mL) was stirred at 60° C. for 16 hours. The mixture was dilutedwith ethyl acetate, and the organic phase was washed with water andbrine and dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash chromatography on silica gel with 0-8% ethylacetate/hexanes.

Example 56B 3-benzyl-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 56Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.34 (br, 1H), 8.24 (d,1H), 7.87 (m, 1H), 7.64 (d, 1H), 7.52 (m, 3H), 7.46 (d, 1H), 7.37 (m,1H), 7.22 (m, 5H), 7.11 (m, 1H), 7.03 (m, 1H), 6.85 (d, 1H), 4.84 (t,2H), 4.46 (s, 2H), 4.13 (t, 2H), 2.31 (m, 2H).

Example 57A ethyl3-(2-methylbenzyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting benzylzinc(II) bromide with(2-methylbenzyl)zinc(II) bromide in EXAMPLE 56A.

Example 57B3-(2-methylbenzyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 57Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br, 1H), 8.24 (d,1H), 7.87 (m, 1H), 7.61 (d, 1H), 7.52 (m, 2H), 7.46 (m, 1H), 7.37 (m,2H), 7.16 (m, 2H), 7.02 (m, 2H), 6.92 (m, 1H), 6.86 (d, 1H), 6.66 (d,1H), 4.88 (t, 2H), 4.40 (s, 2H), 4.13 (t, 2H), 2.38 (s, 3H), 2.34 (m,2H).

Example 58A ethyl3-(3-methylbenzyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting benzyl zinc(II) bromide with(3-methylbenzyl)zinc(II) bromide in EXAMPLE 56A.

Example 58B3-(3-methylbenzyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 58Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.24 (br, 1H), 8.24 (d,1H), 7.87 (m, 1H), 7.62 (d, 1H), 7.52 (m, 3H), 7.46 (m, 1H), 7.37 (m,1H), 7.16 (m, 1H), 7.03 (m, 4H), 6.92 (d, 1H), 6.85 (d, 1H), 4.84 (t,2H), 4.40 (s, 2H), 4.13 (t, 2H), 2.31 (m, 2H), 2.20 (s, 3H).

Example 59A ethyl3-(4-methylbenzyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting benzylzinc(II) bromide with(4-methylbenzyl)zinc(II) bromide in EXAMPLE 56A.

Example 59B3-(4-methylbenzyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 59Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (br, 1H), 8.24 (m,1H), 7.87 (m, 1H), 7.62 (d, 1H), 7.52 (m, 3H), 7.46 (m, 1H), 7.37 (m,1H), 7.16 (m, 1H), 7.11 (d, 1H), 7.01 (m, 3H), 6.85 (d, 1H), 4.84 (t,2H), 4.41 (s, 2H), 4.13 (t, 2H), 2.31 (m, 2H), 2.20 (s, 3H).

Example 60A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-(naphthalen-2-ylmethyl)-1H-indole-2-carboxylate

This example was prepared by substituting benzylzinc(II) bromide with(naphthalen-2-ylmethyl)zinc(II) bromide in EXAMPLE 56A.

Example 60B3-(2-naphthylmethyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 60Ain EXAMPLE 31E. ¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (br, 1H), 8.25 (m,1H), 7.87 (m, 1H), 7.80 (m, 1H), 7.74 (m, 3H), 7.67 (d, 1H), 7.59 (d,1H), 7.52 (m, 2H), 7.41 (m, 5H), 7.18 (m, 1H), 7.02 (m 1H), 6.85 (d,1H), 4.86 (t, 2H), 4.64 (s, 2H), 4.14 (t, 2H), 2.33 (m, 2H).

Example 611-(3-(1-naphthyloxy)propyl)-3-(2-phenylethyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 66 (18 mg), cyclohexene (0.5 mL), Pd/C (10%, 5 mg)in ethanol (2 mL) was heated under microwave conditions (CEM Discover)at 110° C. for 20 minutes, filtered and concentrated. The product waspurified by preparative reverse phaseHPLC (Zorbax SB, C-18, 20% to 100%acetonitrile/water/0.1% trifluoroacetic acid). ¹H NMR (400 MHz, DMSO-d₆)δ 13.15 (br, 1H), 8.23 (m, 1H), 7.87 (m, 1H), 7.68 (m, 1H), 7.53 (m,3H), 7.45 (d, 1H), 7.37 (m, 1H), 7.26 (m, 4H), 7.18 (m, 2H), 7.06 (m1H), 6.85 (d, 1H), 4.83 (t, 2H), 4.12 (t, 2H), 3.30 (t, 2H), 2.83 (t,2H), 2.33 (m, 2H).

Example 621-(3-(1-naphthyloxy)propyl)-3-(3-phenylpropyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 66 with EXAMPLE 67 inEXAMPLE 61. ¹H NMR (400 MHz, DMSO-d₆) δ 13.07 (br, 1H), 8.23 (d, 1H),7.87 (m, 1H), 7.59 (d, 1H), 7.55 (m, 3H), 7.44 (m, 1H), 7.35 (m, 1H),7.26 (m, 2H), 7.18 (m, 4H), 7.06 (m 1H), 6.82 (d, 1H), 4.83 (t, 2H),4.12 (t, 2H), 3.08 (t, 2H), 2.65 (t, 2H), 2.29 (m, 2H), 1.88 (m, 2H).

Example 63A 1-(2-bromoethoxy)naphthalene

This example was prepared by substituting 3-bromopropanol with2-bromoethanol in EXAMPLE 31A.

Example 63B ethyl1-(2-(naphthalen-1-yloxy)ethyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with EXAMPLE 63Aand substituting EXAMPLE 31B with EXAMPLE 50B in EXAMPLE 31C.

Example 63C3-(2-methylphenyl)-1-(2-(1-naphthyloxy)ethyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 63Bin EXAMPLE 31. ¹H NMR (400 MHz, DMSO-d₆) δ 12.82 (br, 1H), 7.88 (m, 2H),7.79 (d, 1H), 7.43 (m, 3H), 7.33 (m, 4H), 7.21 (m, 1H), 7.12 (m, 3H),6.94 (d, 1H), 5.22 (m, 2H), 4.50 (m, 2H), 1.95 (s, 3H).

Example 64A 2-(2-bromoethoxy)naphthalene

This example was prepared by substituting 1-naphthol with 2-naphthol andsubstituting 3-bromopropanol with 2-bromoethanol in EXAMPLE 31A.

Example 64B ethyl1-(2-(naphthalen-2-yloxy)ethyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with EXAMPLE 64Aand substituting EXAMPLE 31B with EXAMPLE 50B in EXAMPLE 31C.

Example 64C3-(2-methylphenyl)-1-(2-(2-naphthyloxy)ethyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 64Bin EXAMPLE 31. ¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (br, 1H), 7.78 (m, 4H),7.43 (m, 1H), 7.37 (m, 1H), 7.29 (m, 4H), 7.21 (m, 1H), 7.14 (m 1H),7.09 (m, 2H), 7.02 (dd, 1H), 5.08 (m, 2H), 4.45 (m, 2H), 1.99 (s, 3H).

Example 65A 1-(2-bromoethoxy)-2,3-dichlorobenzene

This example was prepared by substituting 1-naphthol with2,3-dichlorophenol and substituting 3-bromopropanol with 2-bromoethanolin EXAMPLE 31A.

Example 65B ethyl1-(2-(2,3-dichlorophenoxy)ethyl)-3-ortho-tolyl-1H-indole-2-carboxylate

This example was prepared by substituting EXAMPLE 31A with EXAMPLE 65Aand substituting EXAMPLE 31B with EXAMPLE 50B in EXAMPLE 31C.

Example 65C1-(2-(2,3-dichlorophenoxy)ethyl)-3-(2-methylphenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting EXAMPLE 31D with EXAMPLE 65Bin EXAMPLE 31. ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (br, 1H), 7.75 (d, 1H),7.35 (m, 1H), 7.24 (m, 4H), 7.13 (m 3H), 7.09 (d, 2H), 5.08 (m, 2H),4.48 (m, 2H), 2.01 (s, 3H).

Example 661-(3-(1-naphthyloxy)propyl)-3-((E)-2-phenylvinyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 31C (100 mg), (E)-styrylboronic acid (39 mg), andbis(triphenylphosphine)palladium(II) dichloride (8 mg) in 7:3:3dimethoxyethane:ethanol:1N aqueous LiOH (2 mL) was heated undermicrowave conditions (CEM Discover) at 130° C. for 30 minutes Themixture was quenched with 1NHCl and extracted with ethyl acetate. Theextract was dried (Na₂SO₄), filtered, and concentrated. The concentratewas purified by reverse phaseHPLC (Zorbax SB-C18, 20-100%acetonitrile/water/0.1% trifluoroacetic acid) to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (br, 1H), 8.24 (m, 1H), 8.15(d, 1H), 7.94 (m, 1H), 7.87 (m, 1H), 7.69 (d, 1H), 7.59 (m, 2H), 7.53(m, 2H), 7.46 (m, 1H), 7.40 (m, 3H), 7.28 (m, 3H), 7.21 (m 1H), 6.87 (d,1H), 4.87 (t, 2H), 4.17 (t, 2H), 2.34 (m, 2H).

Example 671-(3-(1-naphthyloxy)propyl)-3-((1E)-3-phenylprop-1-enyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid with(E)-3-phenylprop-1-enylboronic acid in EXAMPLE 66. ¹H NMR (400 MHz,DMSO-d₆) δ 13.37 (br, 1H), 8.22 (d, 1H), 7.87 (m, 2H), 7.61 (d, 1H),7.51 (m, 2H), 7.45 (m, 1H), 7.35 (m, 5H), 7.20 (m, 3H), 7.10 (m, 1H),6.85 (d, 1H), 6.45 (m, 1H), 4.81 (t, 2H), 4.13 (t, 2H), 3.59 (d, 2H),2.30 (m, 2H).

Example 683-((E)-2-cyclohexylvinyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid with(E)-2-cyclohexylvinylboronic acid in EXAMPLE 66. ¹H NMR (400 MHz,DMSO-d₆) δ 13.30 (br, 1H), 8.23 (m, 1H), 7.91 (d, 1H), 7.87 (m, 1H),7.60 (d, 1H), 7.52 (m, 2H), 7.45 (d, 1H), 7.37 (t, 1H), 7.21 (t, 1H),7.12 (t, 1H), 7.07 (dd, 1H), 6.85 (d, 1H), 6.25 (dd, 1H), 4.81 (t, 2H),4.13 (t, 2H), 2.29 (m, 2H), 2.17 (m, 1H), 1.81 (m, 2H), 1.75 (m, 2H),1.65 (m, 1H), 1.33 (m, 2H), 1.22 (m, 3H).

Example 691-(3-(1-naphthyloxy)propyl)-3-(3-(piperidin-1-ylcarbonyl)phenyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid with3-(piperidine-1-carbonyl)phenylboronic acid in EXAMPLE 66. ¹H NMR (400MHz, DMSO-d₆) δ 13.04 (br, 1H), 8.19 (d, 1H), 7.86 (d, 1H), 7.68 (d,1H), 7.44 (m, 9H), 7.26 (t, 1H), 7.11 (t, 1H), 6.88 (d, 1H), 4.88 (t,2H), 4.20 (t, 2H), 3.57 (br, 4H), 2.38 (m, 2H), 1.61 (br, 2H), 1.50 (br,4H).

Example 703-(4-fluoro-3-(morpholin-4-ylcarbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid with4-fluoro-3-(morpholine-4-carbonyl)phenylboronic acid in EXAMPLE 66. ¹HNMR (400 MHz, DMSO-d₆) δ 13.06 (br, 1H), 8.18 (d, 1H), 7.86 (m, 1H),7.69 (d, 1H), 7.45 (m, 8H), 7.27 (m, 1H), 7.12 (t, 1H), 6.88 (d, 1H),4.89 (t, 2H), 4.20 (t, 2H), 3.66 (s, 4H), 3.56 (br, 2H), 3.31 (br, 2H),2.38 (m, 2H).

Example 713-(3-(((2-methoxyethyl)amino)carbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid with3-(2-methoxyethylcarbamoyl)phenylboronic acid in EXAMPLE 66. ¹H NMR (400MHz, DMSO-d₆) δ 13.01 (br, 1H), 8.52 (t, 1H), 8.25 (m, 1H), 7.93 (s,1H), 7.86 (m, 2H), 7.68 (d, 1H), 7.49 (m, 6H), 7.25 (m, 1H), 7.11 (t,1H), 6.89 (d, 1H), 4.89 (t, 2H), 4.20 (t, 2H), 3.46 (m, 4H), 3.26 (s,3H), 2.38 (m, 2H).

Example 723-(3-((dimethylamino)sulfonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid with3-(N,N-dimethylsulfamoyl)phenylboronic acid in EXAMPLE 66. ¹H NMR (400MHz, DMSO-d₆) δ 13.20 (br, 1H), 8.20 (m, 1H), 7.87 (m, 1H), 7.73 (m,5H), 7.47 (m, 5H), 7.28 (m, 1H), 7.17 (m, 1H), 6.87 (m, 1H), 4.89 (m,2H), 4.18 (m, 2H), 2.66 (s, 6H), 2.40 (m, 2H).

Example 733-(3-(morpholin-4-ylmethyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by substituting (E)-styrylboronic acid with4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine inEXAMPLE 66. ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (br, 1H), 8.24 (m, 1H),7.88 (m, 1H), 7.70 (d, 1H), 7.53 (m, 8H), 7.39 (t, 1H), 7.28 (m, 1H),7.13 (t, 1H), 6.89 (d, 1H), 4.90 (t, 2H), 4.42 (s, 2H), 4.20 (t, 2H),3.98 (br, 2H), 3.65 (br, 2H), 3.29 (br, 2H), 3.14 (br, 2H), 2.38 (m,2H).

Example 74A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-(piperidin-1-yl)-1H-indole-2-carboxylate

A mixture of EXAMPLE 31C (100 mg), piperidine (57 mg),tris(dibenzylideneacetone)dipalladium(0) (20 mg),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (26 mg) and Cs₂CO₃ (216 mg)in toluene (2 mL) was heated at 100° C. for 48 hours. The mixture wasdiluted with ethyl acetate and was washed with water and brine. Theorganic phase was dried (Na₂SO₄) filtered, and concentrated. Theconcentrate was purified by flash chromatography on silica gel with0-10% ethyl acetate/hexanes.

Example 74B1-(3-(1-naphthyloxy)propyl)-3-piperidin-1-yl-1H-indole-2-carboxylic acid

A mixture of EXAMPLE 74A (30 mg) in 1N aqueous LiOH/methanol/THF (1 mL/1mL/1 mL) was stirred at room temperature overnight. The reaction mixturewas acidified with 1NHCl (1 mL), and extracted with ethyl acetate. Theorganic phase was dried (Na₂SO₄) filtered, and concentrated. Theconcentrate was purified by reverse phaseHPLC (Zorbax SB-C18, 20-100%acetonitrile/water/0.1% trifluoroacetic acid). ¹H NMR (400 MHz, DMSO-d₆)δ 16.82 (s, 1H), 8.08 (d, 1H), 7.96 (d, 1H), 7.85 (d, 1H), 7.69 (d, 1H),7.48 (m, 3H), 7.36 (t, 1H), 7.24 (m, 1H), 7.13 (t, 1H), 6.83 (t, 1H),4.89 (t, 2H), 4.16 (t, 2H), 3.24 (br, 4H), 2.33 (m, 2H), 1.70 (br, 6H).

Example 75A ethyl3-morpholino-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by substituting piperidine with morpholine inEXAMPLE 74A.

Example 75B3-morpholin-4-yl-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 74A with EXAMPLE 75Ain EXAMPLE 74B. ¹H NMR (400 MHz, DMSO-d₆) δ 15.74 (s, 1H), 8.10 (d, 1H),7.93 (d, 1H), 7.85 (m, 1H), 7.71 (d, 1H), 7.50 (m, 2H), 7.44 (d, 1H),7.36 (t, 1H), 7.25 (m, 1H), 7.14 (m, 1H), 6.84 (d, 1H), 4.89 (t, 2H),4.16 (t, 2H), 3.81 (t, 4H), 3.26 (t, 4H), 2.33 (m, 2H).

Example 76A ethyl1-(3-(naphthalen-1-yloxy)propyl)-3-(3-(trifluoromethoxy)phenylamino)-1H-indole-2-carboxylate

This example was prepared by substituting piperidine with3-(trifluoromethoxy)aniline in EXAMPLE 74A.

Example 76B1-(3-(1-naphthyloxy)propyl)-3-((3-(trifluoromethoxy)phenyl)amino)-1H-indole-2-carboxylic acid

This example was prepared by substituting EXAMPLE 74A with EXAMPLE 76Ain EXAMPLE 74B. ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (br, 1H), 8.24 (m,1H), 8.08 (br, 1H), 7.87 (m, 1H), 7.64 (d, 1H), 7.52 (m, 2H), 7.46 (d,2H), 7.37 (t, 1H), 7.28 (d, 1H), 7.20 (m, 2H), 7.00 (t, 1H), 6.85 (d,1H), 6.74 (m, 2H), 6.63 (d, 1H), 4.85 (t, 2H), 4.15 (t, 2H), 2.32 (m,2H).

Example 77A ethyl3-(4-(methoxycarbonyl)piperidin-1-yl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

This example was prepared by replacing piperidine with methylpiperidine-4-carboxylate in EXAMPLE 74A.

Example 77B3-(4-carboxypiperidin-1-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

This example was prepared by replacing EXAMPLE 74A with EXAMPLE 77A inEXAMPLE 74B. ¹H NMR (400 MHz, DMSO-d₆) δ 16.42 (s, 1H), 12.39 (s, 1H),8.08 (d, 1H), 7.94 (d, 1H), 7.85 (m, 1H), 7.70 (d, 1H), 7.48 (m, 3H),7.36 (t, 1H), 7.25 (m, 1H), 7.13 (t, 1H), 6.83 (d, 1H), 4.89 (t, 2H),4.15 (t, 2H), 3.42 (m, 2H), 3.13 (m, 2H), 2.69 (m, 1H), 2.33 (m, 2H),2.05 (m, 2H), 1.72 (m, 2H).

Example 793-anilino-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid Example 79A methyl1-(3-(naphthalen-1-yloxy)propyl)-3-(phenylamino)-4-o-tolyl-1H-indole-2-carboxylate

A mixture of EXAMPLE 126C (42 mg, 0.079 mmol), aniline (8.71 μl, 0.095mmol), xantphos (4.14 mg, 7.15 μmol), diacetoxypalladium (1.071 mg, 4.77μmol) and dioxane (2 ml) was heated at 160° C. under microwave conditionfor 30 min. The precipitate was filtered off and the filtrateconcentrated. The residue was purified by flash chromatography, elutingwith 1/1 dichloromethane/hexane to provide the desired product.

Example 79B3-anilino-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

A mixture EXAMPLE 79A (34.1 mg) and sodium hydroxide (0.252 ml) intetrahydrofuran (1 ml) and methanol (1.000 ml) was stirred overnight andacidified with HCl. The resulting mixture was concentrated and theresidue purified by RPHPLC (mobile phase: 10%-100% acetonitrile in 0.1%TFA aqueous solution during 60 min) on a C18 column. ¹H NMR (400 MHz,dimethyl sulfoxide-D₆) δ 13.11 (s, 1H), 8.21-8.31 (m, 1H), 7.86-7.90 (m,1H), 7.65 (d, J=7.98 Hz, 1H), 7.49-7.57 (m, 2H), 7.44-7.49 (m, 1H),7.36-7.42 (m, 1H), 7.26 (dd, J=8.29, 7.06 Hz, 1H), 6.92-7.00 (m, 1H),6.80-6.91 (m, 4H), 6.70-6.78 (m, 3H), 6.63 (s, 1H), 6.46 (t, J=7.21 Hz,1H), 6.06 (d, J=7.67 Hz, 2H), 4.75-5.07 (m, 2H), 4.20 (t, J=5.68 Hz,2H), 2.39 (t, J=6.14 Hz, 2H), 1.87 (s, 3H).

Example 80 3-(3-(1-naphthylthio)cyclohexyl)-1H-indole-2-carboxylic acidExample 80A ethyl 3-(3-oxocyclohexyl)-1H-indole-2-carboxylate

Ethyl 1H-indole-2-carboxylate (2.953 g) and cyclohex-2-enone (1.004 mL)were added to acetonitrile (50 mL). Bismuth (III)trifluoromethanesulfonate (341 mg) was added, and the solution washeated at 65° C. for two days. The solution was cooled, concentrated,and purified by flash column chromatography on silica gel with 10%increasing to 20% ethyl acetate in hexanes to provide the titlecompound.

Example 80B ethyl 3-(3-hydroxycyclohexyl)-1H-indole-2-carboxylate

EXAMPLE 80A (931 mg) was added to methanol (20 mL), cooled to 0° C., andtreated with sodium borohydride (247 mg). The solution was mixed at 0°C. for one hour, quenched with 1 MHCl, and extracted with 70% ethylacetate (in hexanes). The solution was dried with brine and anhydroussodium sulfate. After filtration, the solvent was removed under vacuumto provide the title compound.

Example 80C ethyl3-(3-(naphthalen-1-ylthio)cyclohexyl)-1H-indole-2-carboxylate

1,1′-(azodicarbonyl)-dipiperidine (188 mg) was added to tetrahydrofuran(5 mL), cooled to 0° C., and treated with trimethylphosphine (1M intoluene, 0.746 mL). The solution was mixed at 0° C. for 15 minutes.Naphthalene-1-thiol (120 mg) was added followed by EXAMPLE 80B (195 mg).The solution was allowed to warm to ambient temperature and mixovernight. The solution was concentrated and purified by flash columnchromatography on silica gel with 10% ethyl acetate in hexanes toprovide the title compound.

Example 80D 3-(3-(1-naphthylthio)cyclohexyl)-1H-indole-2-carboxylic acid

EXAMPLE 80C (64 mg) was dissolved in tetrahydrofuran (1 mL), water (0.33mL), and methanol (0.33 mL). Lithium hydroxide monohydrate (31 mg) wasadded, and the solution was mixed at ambient temperature overnight. Thesolution was made slightly acidic using 1 MHCl, extracted with ethylacetate, and dried with anhydrous sodium sulfate. After filtration, thesolvent was removed under vacuum to provide the title compound. ¹H NMR(300 MHz, dimethyl sulfoxide-d₆) δ 12.95 (broad s, 1H), 11.35 (s, 1H),8.52 (d, 1H), 7.94 (dd, 1H), 7.84 (dd, 1H), 7.81 (d, 1H), 7.64-7.52 (m,3H), 7.46 (dd, 1H), 7.38 (d, 1H), 7.17 (td, 1H), 6.97 (td, 1H), 4.33 (m,1H), 3.85 (broad s, 1H), 2.07-1.86 (m, 5H), 1.83-1.65 (m, 3H).

Example 81 3-(3-(1-naphthyloxy)cyclohexyl)-1H-indole-2-carboxylic acidExample 81A ethyl3-(3-(naphthalen-1-yloxy)cyclohexyl)-1H-indole-2-carboxylate

The title compound was prepared by substituting diethylazodicarboxylate, triphenylphosphine, and naphthalene-1-ol for1,1′-(azodicarbonyl)-dipiperidine, trimethylphosphine, andnaphthalene-1-thiol, respectively, in EXAMPLE 80C.

Example 81B 3-(3-(1-naphthyloxy)cyclohexyl)-1H-indole-2-carboxylic acid

The title compound was prepared by substituting EXAMPLE 81A for EXAMPLE80C in EXAMPLE 80D. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 12.94(broad s, 1H), 11.34 (s, 1H), 8.47 (m, 1H), 7.89-7.83 (m, 2H), 7.54 (t,2H), 7.46-7.36 (m, 3H), 7.20 (t, 1H), 7.00 (m, 2H), 5.06 (broad s, 1H),4.54 (tt, 1H), 2.44 (td, 1H), 2.21-2.08 (m, 4H), 1.83-1.75 (m, 3H).

Example 881-(2-methylbenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.06 (s, 1H), 8.18-8.25 (m,1H), 7.84-7.90 (m, 1H), 7.78 (d, J=7.80 Hz, 1H), 7.48-7.55 (m, 2H),7.43-7.48 (m, 1H), 7.34-7.41 (m, 2H), 7.24 (t, J=7.63 Hz, 1H), 7.18 (d,J=7.46 Hz, 1H), 6.99-7.09 (m, 2H), 6.87 (t, J=7.46 Hz, 2H), 5.92 (d,J=7.46 Hz, 1H), 5.78 (s, 2H), 4.20 (t, J=6.10 Hz, 2H), 3.39 (t, J=7.5Hz, 2H), 2.40 (s, 3H), 2.20-2.29 (m, J=1.70 Hz, 2H).

Example 891-(2-(dimethylamino)ethyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.04 (bs, 1H), 8.18-8.25 (m,1H), 7.81-7.91 (m, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.48-7.58 (m, 3H), 7.45(d, J=7.9 Hz, 1H), 7.34-7.42 (m, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.00 (t,J=7.5 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 4.79 (s, 1H), 4.56 (t, J=5.9 Hz,2H), 4.17 (t, J=6.1 Hz, 2H), 3.66 (t, J=5.8 Hz, 2H), 2.10-2.25 (m, 2H).

Example 901-(3-methylbenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.17 (s, 1H), 8.14-8.28 (m,1H), 7.79-7.93 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.42-7.57 (m, 3H),7.34-7.40 (m, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H),6.96-7.06 (m, 2H), 6.83-6.91 (m, 2H), 6.71 (d, J=7.5 Hz, 1H), 5.79 (s,2H), 4.17 (t, J=6.1 Hz, 2H), 3.33-3.41 (m, 2H), 2.24 (s, 2H), 2.19 (s,3H).

Example 911-(4-methylbenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.14 (s, 1H), 8.10-8.28 (m,1H), 7.79-7.95 (m, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.41-7.57 (m, 4H),7.33-7.41 (m, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.02 (t, J=7.7 Hz, 4H), 6.88(t, J=7.9 Hz, 4H), 5.77 (s, 2H), 4.17 (t, J=6.1 Hz, 2H), 3.32-3.39 (m,2H), 2.21-2.25 (m, 2H), 2.20 (s, 3H).

Example 921-(1,1′-biphenyl-2-ylmethyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.04 (s, 1H), 8.09-8.25 (m,1H), 7.81-7.90 (m, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.41-7.56 (m, 8H),7.33-7.41 (m, 1H), 7.18-7.31 (m, 4H), 6.99-7.13 (m, 2H), 6.87 (d, J=6.8Hz, 1H), 6.17 (d, J=7.8 Hz, 1H), 5.71 (s, 2H), 4.18 (t, J=6.1 Hz, 2H),3.33-3.41 (m, 2H), 2.15-2.28 (m, 2H).

Example 931-(1,1′-biphenyl-3-ylmethyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.12 (s, 1H), 8.11-8.34 (m,1H), 7.80-7.92 (m, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.20-7.61 (m, 15H), 7.02(t, J=7.5 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 6.85 (d, J=6.8 Hz, 1H), 5.91(s, 2H), 4.18 (t, J=6.1 Hz, 2H), 3.31-3.46 (m, 2H), 2.12-2.34 (m, 2H).

Example 94 1-(1,1′-biphenyl-4-ylmethyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.20 (s, 1H), 8.13-8.30 (m,1H), 7.80-7.94 (m, 1H), 7.68-7.81 (m, 1H), 7.22-7.60 (m, 14H), 6.95-7.13(m, 3H), 6.88 (d, J=6.4 Hz, 1H), 5.88 (s, 2H), 4.19 (t, J=6.1 Hz, 2H),3.38 (t, J=7.5 Hz, 2H), 2.15-2.32 (m, 2H).

Example 951-(2,4-dimethylbenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.03 (s, 1H), 8.18-8.29 (m,1H), 7.81-7.93 (m, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.31-7.60 (m, 5H),7.17-7.29 (m, 1H), 6.94-7.09 (m, 2H), 6.88 (d, J=6.4 Hz, 1H), 6.66 (d,J=7.8 Hz, 1H), 5.84 (d, J=7.8 Hz, 1H), 5.73 (s, 2H), 4.19 (t, J=6.1 Hz,2H), 3.38 (t, J=7.5 Hz, 2H), 2.35 (s, 3H), 2.18-2.32 (m, 2H), 2.16 (s,3H).

Example 961-(4-carboxybenzyl)-3-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.04 (s, 1H), 12.93 (s, 1H),8.06-8.30 (m, 1H), 7.69-7.94 (m, 4H), 7.43-7.58 (m, 4H), 7.33-7.41 (m,1H), 7.27 (t, J=7.1 Hz, 1H), 6.97-7.12 (m, 3H), 6.88 (d, J=6.8 Hz, 1H),5.89 (s, 2H), 4.18 (t, J=5.9 Hz, 2H), 3.34-3.44 (m, 2H), 2.13-2.32 (m,2H).

Example 971-((2S)-2-methyl-3-(1-naphthyloxy)propyl)-4-(2-methylphenyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 12.91 (s, 1H), 8.06-8.31 (m,1H), 7.77-7.95 (m, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.42-7.59 (m, 3H),7.18-7.43 (m, 5H), 6.97 (d, J=6.7 Hz, 1H), 6.71-6.89 (m, 2H), 4.82-4.95(m, 1H), 4.66-4.83 (m, 1H), 3.97-4.13 (m, 2H), 2.59-2.78 (m, 1H),1.98-2.15 (m, 3H), 1.07 (d, J=6.7 Hz, 3H).

Example 981-((2R)-2-methyl-3-(1-naphthyloxy)propyl)-4-(2-methylphenyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 12.91 (s, 1H), 8.06-8.31 (m,1H), 7.77-7.95 (m, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.42-7.59 (m, 3H),7.18-7.43 (m, 5H), 6.97 (d, J=6.7 Hz, 1H), 6.71-6.89 (m, 2H), 4.82-4.95(m, 1H), 4.66-4.83 (m, 1H), 3.97-4.13 (m, 2H), 2.59-2.78 (m, 1H),1.98-2.15 (m, 3H), 1.07 (d, J=6.7 Hz, 3H).

Example 993-(3-(1-naphthyloxy)propyl)-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 13.30 (br. s, 1H) 8.61-8.69(m, 2H) 8.19 (d, 1H) 7.78-7.90 (m, 2H) 7.26-7.57 (m, 8H) 7.10 (t, 1H)6.89 (d, 1H) 6.02 (s, 2H) 4.21 (t, 2H) 3.40 (t, 2H) 2.21-2.29 (m, 2H).

Example 1003-(3-(1-naphthyloxy)propyl)-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 8.51-8.57 (m, 1H) 8.17-8.23(m, 1H) 7.84-7.89 (m, 1H) 7.71-7.79 (m, 2H) 7.42-7.57 (m, 4H) 7.38 (t,1H) 7.24-7.35 (m, 2H) 7.06 (t, 1H) 6.89 (d, 1H) 6.77 (d, 1H) 5.91 (s,2H) 4.19 (t, 2H) 3.38 (t, 2H) 2.19-2.30 (m, 2H).

Example 1011-(4-methoxybenzyl)-3-(2-(1-naphthyloxy)ethoxy)-1H-indole-2-carboxylicacid Example 101A ethyl 3-bromo-1H-1-indole-2-carboxylate

To a stirred solution of ethyl 1H-indole-2-carboxylate (9.45 g) intetrahydrofuran (100 mL) was added N-bromosuccinimide (8.89 g, 50 mmol).The mixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under vacuum and the residue was dissolved with water (100ml) and diethyl ether (300 ml). The organic layer was washed with waterbrine and dried over Na₂SO₄. After filtration, concentration of solventafforded the title compound.

Example 101B ethyl 3-bromo-1-(4-methoxybenzyl)-1H-indole-2-carboxylate

To a solution of EXAMPLE 101A (5.9 g) in N,N-dimethylfomamide (50 mL)was added 1-(bromomethyl)-4-methoxybenzene (4.85 g) and Cs₂CO₃ (25 g).The mixture was stirred overnight at room temperature. The mixture wasdiluted with ether (300 mL) and water (200 mL). The aqueous layer wasextracted with ether twice. The combined extracts were washed with water(×3), brine and dried over Na₂SO₄. Concentration of the solvent gaveEXAMPLE 101B.

Example 101C ethyl1-(4-methoxybenzyl)-3-(2-(naphthalen-1-yloxy)ethoxy)-1H-indole-2-carboxylate

To a solution of EXAMPLE 101B (388 mg) and 2-(naphthalen-1-yloxy)ethanol(188 mg) in toluene (3 ml) was added1,1c-binaphthyl-2-yldi-tert-butylphosphine (7.5 mg), palladium(II)acetate (5 mg) and Cs₂CO₃ (488 mg). The mixture was purged with argonand stirred at room temperature and then heated at 80° C. overnight.After this time the mixture was diluted with ethyl acetate (200 mL) andwashed with water, brine and dried over Na₂SO₄. After concentration ofthe solvent, the residue was loaded on a silica gel column and elutedwith 5% ethyl acetate in hexane to give EXAMPLE 101C.

Example 101D1-(4-methoxybenzyl)-3-(2-(1-naphthyloxy)ethoxy)-1H-indole-2-carboxylicacid

To a solution of EXAMPLE 101C (80 mg) in tetrahydrofuran (2 ml),methanol (1 ml) and water (1 ml) was added LiOH (100 mg). The mixturewas stirred at room temperature overnight. The mixture was thenacidified with 5% HCl and extracted with ethyl acetate (200 ml). Theorganic layer was washed with water, brine and dried over Na₂SO₄. Afterconcentration of the solvent, the residue was dissolved in DMSO/methanol(1:1, 1.5 ml) and purified via reverse phaseHPLC. ¹H NMR (500 MHz,dimethyl sulfoxide-d₆) δ 12.99 (m, 1H), 8.01 (m, 1H), 7.86 (m, 1H), 7.73(m, 1H), 7.46 (m, 6H), 7.27 (m, 1H), 6.98 (m, 3H), 6.74 (m, 2H), 5.70(s, 2H), 4.64 (m, 2H), 4.48 (m, 2H), 3.67 (s, 3H).

Example 1021-(4-methoxybenzyl)-3-(3-(1-naphthyloxy)prop-1-ynyl)-1H-indole-2-carboxylicacid Example 102A ethyl1-(4-methoxybenzyl)-3-(3-(naphthalen-1-yloxy)prop-1-ynyl)-1H-indole-2-carboxylate

To a solution of EXAMPLE 101B (3.89 g) in acetonitrile (20 ml) was addedPd(PhCN)₂Cl₂ (38 mg),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (143 mg), andCs₂CO₃ (3.91 g). The mixture was purged with argon and stirred at roomtemperature for 25 minutes. After this time,1-(prop-2-ynyloxy)naphthalene (2.2 g) was added to the mixture which waspurged with argon again. The mixture was then stirred at 80° C. for 3hours. The mixture was diluted with ethyl acetate (300 ml) and washedwith water, brine and dried over Na₂SO₄. After filtration, the solventwas concentrated and the residue was loaded on a silica gel column andeluted with 5% ethyl acetate in hexane to give EXAMPLE 102A.

Example 102B1-(4-methoxybenzyl)-3-(3-(1-naphthyloxy)prop-1-ynyl)-1H-indole-2-carboxylicacid

The title compound was prepared via ester hydrolysis as detailed in theprocedure for EXAMPLE 101D, substituting EXAMPLE 102A for EXAMPLE 101C.¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 13.57 (m, 1H), 8.20 (m, 1H),7.90 (m, 1H), 7.57 (m, 6H), 7.25 (m, 3H), 6.98 (d, 2H), 6.80 (d, 2H),5.78 (s, 2H), 5.36 (s, 2H), 3.66 (s, 3H).

Example 1034-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 12.92 (m, 1H), 8.26 (m, 1H),7.87 (m, 1H), 7.65 (m, 1H), 7.38 (m, 9H), 6.98 (m, 1H), 6.89 (m, 1H),6.78 (s, 1H), 4.91 (m, 2H), 4.19 (m, 2H), 2.37 (m, 2H), 2.09 (s, 3H).

Example 1044-(2,6-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 12.89 (m, 1H), 8.28 (m, 1H),7.87 (m, 1H), 7.37 (m, 9H), 6.86 (m, 2H), 6.58 (m, 1H), 4.91 (t, 2H),4.17 (t, 2H), 2.38 (m, 2H), 1.87 (s, 6H).

Example 1051-(3-(1-naphthyloxy)propyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.25 (m, 1H), 7.88 (m, 1H),7.41 (m, 6H), 6.91 (m, 4H), 4.89 (m, 2H), 4.20 (m, 2H), 3.76 (s, 3H),2.35 (m, 2H), 2.10 (s, 3H), 2.01 (s, 3H).

Example 1061-(3-(1-naphthyloxy)propyl)-4-(2-oxocyclohexyl)-1H-indole-2-carboxylicacid Example 106A ethyl 4-bromo-1H-indole-2-carboxylate

To a solution of ethyl bromoacetate (42 g) in ethanol (120 mL) was addeda solution of NaN₃ (25 g) in water (60 ml). The mixture was stirred atreflux for 4 hours. The mixture was concentrated under vacuum and theresidue was partitioned between ether (300 mL) and water (200 mL). Theaqueous layer was further extracted with ether. The combined extractswere washed with water (×3), brine and dried over Na₂SO₄. Afterfiltration, careful concentration of solvent gave ethyl azidoacetate (26g) which was dissolved in ethanol (100 ml) and 2-bromobenzaldehyde (12.5g) was added to the solution which was then added dropwise to a cooled(−15° C.) solution of sodium ethoxide (prepared from Na (5.2 g) andethanol (60 ml)). The mixture was stirred at 0° C. for 4 hours beforepoured into a mixture of ice and saturated aqueous NH₄Cl solution. Themixture was filtered and the precipitate was washed with water anddissolved in ethyl acetate and dried over Na₂SO₄. Concentration ofsolvent gave crude intermediate, which was dissolved in xylene (100 ml)and added dropwise to refluxing xylene under nitrogen. After theaddition, the mixture was stirred at reflux overnight. Concentration ofthe mixture under vacuum gave the crude product, which was purified bysilica gel chromatography (2% ethyl acetate in hexane).

Example 106B ethyl4-bromo-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

To a solution of EXAMPLE 106A (5.5 g) in N,N-dimethylformamide (60 mL)was added 1-(3-bromopropoxy)naphthalene (5.4 g) and Cs₂CO₃ (22 g). Themixture was stirred overnight at room temperature. The mixture wasdiluted with ether (300 mL) and water (200 mL). The aqueous layer wasextracted with ether twice. The combined extracts were washed with water(×3), brine and dried over Na₂SO₄. Concentration of the mixture gavecrude product, which was purified by flash chromatography (2% ethylacetate in hexane).

Example 106C ethyl1-(3-(naphthalen-1-yloxy)propyl)-4-(2-oxocyclohexyl)-1H-indole-2-carboxylate

To a solution of EXAMPLE 106B (438 mg) and cyclohexanone (196 mg) indioxane (3 ml) was added tris(dibenzylideneacetone)dipalladium(0) (5mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 7 mg)and Cs₂CO₃ (652 mg). The mixture was stirred at 80° C. under nitrogenovernight. After cooling, the reaction mixture was diluted with ethylacetate and shaken with water. The product was extracted with ether (200ml×3). The combined organic extracts were washed with water, brine, anddried over Na₂SO₄. After filtration, concentration of the mixture andflash column purification (3% ethyl acetate in hexane) provided EXAMPLE106C.

Example 106D1-(3-(1-naphthyloxy)propyl)-4-(2-oxocyclohexyl)-1H-indole-2-carboxylicacid

The title compound was prepared via ester hydrolysis as detailed in theprocedure for EXAMPLE 101D, substituting EXAMPLE 106C for EXAMPLE 101C.¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 12.86 (m, 1H), 8.28 (m, 1H),7.87 (m, 1H), 7.46 (m, 5H), 7.17 (m, 2H), 6.89 (m, 2H), 4.87 (m, 2H),4.17 (m, 3H), 2.70 (m, 1H), 2.04 (m, 9H).

Example 1074-(2-methylphenyl)-3-(morpholin-4-ylmethyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid Example 107A methyl 4-bromo-3-formyl-1H-indole-2-carboxylate

To a solution of methyl 4-bromo-1H-indole-2-carboxylate (4.09 g) indichloromethane (60 mL) was added a mixture of POCl₃ (3.7 g) andN,N-dimethylformamide (1.76 g). The mixture was stirred at refluxovernight. The mixture was diluted with ethyl acetate (300 mL) and 2Msodium acetate solution in water (200 mL) The mixture was stirredthoroughly for 1 hour. The aqueous layer was extracted with ethylacetate. The combined extracts were washed with water (×3), brine anddried over Na₂SO₄. After filtration, concentration of the mixture gavethe title compound, which was used in next step without purification.

Example 107B methyl4-bromo-3-formyl-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

To a solution of EXAMPLE 107A (1.76 g) in N,N-dimethylformamide (10 mL)was added 1-(3-bromopropoxy)naphthalene (1.66 g) and Cs₂CO₃ (6.10 g).The mixture was stirred for 3 days at room temperature. The mixture wasdiluted with ethyl acetate (300 mL) and water (200 mL). The aqueouslayer was extracted with ethyl acetate. The combined organic extractswere washed with water (×3) and brine and dried over Na₂SO₄. Afterfiltration, concentration of solvent gave crude product, which waspurified by column chromatography (5% ethyl acetate in hexane).

Example 107C methyl3-formyl-1-(3-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indole-2-carboxylate

To a mixture of EXAMPLE 107B (0.5 g) and o-tolylboronic acid (175 mg) intetrahydrofuran (5 ml) was addedtris(dibenzylideneacetone)dipalladium(0) (25 mg),tri-t-butyl-phosphonium tetrafluoroborate (16 mg) and CsF (489 mg). Themixture was purged with Argon and stirred at room temperature for 24hours. The mixture was diluted with ethyl acetate (200 mL) and washedwith water and brine and dried over Na₂SO₄. After filtration,concentration of the solvent and column purification (5% ethyl acetatein hexane) provided EXAMPLE 107C.

Example 107D4-(2-methylphenyl)-3-(morpholin-4-ylmethyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

To a solution of EXAMPLE 107C (50 mg) in dichloroethane (3 ml) was addedsodium triacetoxyborohydride (35 mg) and morpholine (15 mg). The mixturewas stirred overnight at room temperature. The reaction mixture wasdiluted with ethyl acetate (200 ml) and washed with water, brine, anddried over Na₂SO₄. The residue was dissolved in tetrahydrofuran (4 ml),methanol (2 mL) and water (2 ml) and LiOH (100 mg) was added. Themixture was stirred at room temperature overnight. The mixture wasconcentrated and the residue neutralized with aqueous NH₄Cl andextracted with ethyl acetate (100 mL×3). The combined extracts weredried and concentrated to give crude product, which was purified byRPHPLC. ¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.25 (m, 1H), 7.86 (m,2H), 7.45 (m, 9H), 6.93 (m, 2H), 4.99 (m, 2H), 4.47 (m, 1H), 4.25 (t,2H), 3.60 (m, 10H), 2.43 (m, 2H), 1.92 (s, 3H).

Example 1084-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-(pyrrolidin-1-ylmethyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.84 (m, 1H), 8.24 (m, 1H),7.86 (m, 2H), 7.48 (m, 9H), 6.95 (m, 2H), 4.99 (m, 2H), 4.47 (m, 1H),4.26 (m, 2H), 2.77 (m, 2H), 2.42 (m, 2H), 1.92 (s, 3H), 1.61 (m, 4H).

Example 1093-((dimethylamino)methyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.58 (m, 1H), 8.27 (m, 1H),7.84 (m, 2H), 7.44 (m, 9H), 6.93 (m, 2H), 5.00 (m, 2H), 4.37 (m, 1H),4.24 (m, 2H), 2.40 (m, 6H), 2.15 (m, 3H), 1.92 (s, 3H).

Example 1103-(((cyclohexylmethyl)amino)methyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.35 (m, 2H), 7.90 (m, 1H),7.77 (m, 1H), 7.43 (m, 9H), 6.93 (m, 2H), 4.95 (m, 2H), 4.22 (m, 3H),3.17 (m, 2H), 2.36 (m, 2H), 2.20 (m, 1H), 2.06 (m, 1H), 1.91 (m, 3H),1.56 (m, 4H), 1.18 (m, 3H), 0.76 (m, 2H).

Example 1114-(2-morpholin-4-ylcyclohexyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 9.69 (m, 1H), 8.24 (m, 1H),7.88 (m, 1H), 7.49 (m, 7H), 7.21 (m, 1H), 6.86 (m, 1H), 4.88 (m, 2H),4.18 (m, 3H), 4.04 (m, 2H), 3.82 (m, 4H), 2.91 (m, 4H), 2.27 (m, 3H),1.92 (m, 3H), 1.49 (m, 3H).

Example 1124-(2-methylphenyl)-3-((4-methylpiperazin-1-yl)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.25 (m, 1H), 7.88 (m, 1H),7.73 (m, 1H), 7.40 (m, 8H), 6.90 (m, 2H), 6.65 (m, 1H), 4.90 (m, 2H),4.23 (m, 3H), 3.36 (m, 4H), 2.85 (m, 3H), 2.67 (s, 3H), 2.37 (m, 3H),1.95 (s, 3H).

Example 1134-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-(piperidin-1-ylmethyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.26 (m, 1H), 7.86 (m, 2H),7.45 (m, 10H), 6.93 (m, 2H), 4.97 (m, 2H), 4.46 (m, 1H), 4.25 (m, 2H),3.72 (m, 2H), 3.10 (m, 3H), 2.40 (m, 2H), 1.92 (s, 3H), 1.35 (m, 6H).

Example 1144-(2-methylphenyl)-3-((4-methylpiperidin-1-yl)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.27 (m, 1H), 7.86 (m, 2H),7.44 (m, 8H), 6.95 (m, 2H), 4.98 (m, 2H), 4.44 (m, 1H), 4.24 (m, 2H),3.70 (m, 2H), 3.18 (m, 2H), 2.40 (m, 2H), 1.91 (s, 3H), 1.36 (m, 8H),0.79 (m, 3H).

Example 1153-((benzyl(methyl)amino)methyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.23 (m, 1H), 7.83 (m, 2H),7.45 (m, 10H), 7.19 (m, 5H), 6.91 (m, 2H), 5.01 (m, 2H), 4.24 (m, 2H),2.37 (m, 3H), 1.95 (m, 2H).

Example 1164-(2-methylphenyl)-3-((methyl(pyridin-2-ylmethyl)amino)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.57 (m, 1H), 8.23 (m, 1H),7.84 (m, 3H), 7.47 (m, 8H), 7.24 (m, 4H), 6.91 (m, 2H), 4.94 (m, 2H),4.24 (m, 2H), 4.12 (m, 2H), 2.37 (m, 4H), 2.12 (s, 3H), 1.88 (s, 3H).

Example 1174-(2-methylphenyl)-3-((methyl(pyridin-3-ylmethyl)amino)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 9.32 (m, 1H), 8.78 (m, 1H),8.69 (m, 1H), 8.25 (m, 1H), 8.01 (m, 1H), 7.89 (m, 1H), 7.80 (m, 1H),7.66 (m, 1H), 7.43 (m, 6H), 7.20 (m, 4H), 6.93 (m, 2H), 4.98 (m, 2H),4.28 (m, 2H), 2.39 (m, 2H), 2.00 (s, 3H), 1.86 (s, 3H).

Example 1184-(2-methylphenyl)-3-((methyl(pyridin-4-ylmethyl)amino)methyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.76 (m, 2H), 8.23 (m, 1H),7.82 (m, 2H), 7.48 (m, 7H), 7.21 (m, 4H), 6.90 (m, 2H), 4.96 (m, 2H),4.25 (m, 2H), 2.39 (m, 2H), 2.02 (s, 3H), 1.87 (s, 3H).

Example 1194-(2-(4-fluorophenyl)cyclohex-1-en-1-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, chloroform-d) δ 8.36 (m, 1H), 7.81 (m, 1H), 7.52 (m,2H), 7.42 (m, 1H), 7.32 (m, 2H), 7.20 (m, 1H), 6.96 (m, 3H), 6.65 (m,4H), 4.81 (m, 2H), 4.06 (m, 2H), 2.51 (m, 4H), 2.38 (m, 2H), 1.89 (m,4H).

Example 1204-(2-methyl-6-nitrophenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, chloroform-d) δ 8.39 (m, 1H), 7.80 (m, 2H), 7.49 (m,7H), 7.29 (m, 1H), 7.03 (s, 1H), 6.92 (m, 1H), 6.72 (m, 1H), 4.92 (m,2H), 4.15 (m, 2H), 2.50 (m, 2H), 2.07 (s, 3H).

Example 1214-(2-chloro-6-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, dimethyl sulfoxide-d₆) δ 8.28 (m, 1H), 7.88 (m, 1H),7.65 (m, 1H), 7.40 (m, 8H), 6.89 (m, 2H), 6.63 (s, 1H), 4.90 (m, 2H),4.20 (m, 2H), 2.38 (m, 2H), 1.94 (s, 3H).

Example 1221-(3-(1-naphthyloxy)propyl)-4-(2-(4-nitrophenyl)cyclohex-1-en-1-yl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, chloroform-d) δ 8.37 (m, 1H), 7.81 (m, 3H), 7.52 (m,2H), 7.32 (m, 5H), 7.10 (m, 2H), 6.99 (m, 1H), 6.68 (m, 2H), 4.84 (m,2H), 4.06 (m, 2H), 2.54 (m, 4H), 2.42 (m, 2H), 1.93 (m, 4H).

Example 1234-(2-(3-methoxyphenyl)cyclohex-1-en-1-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, chloroform-d) δ 8.36 (m, 1H), 7.80 (m, 1H), 7.51 (m,2H), 7.30 (m, 4H), 7.02 (m, 1H), 6.89 (m, 1H), 6.65 (m, 3H), 6.48 (m,2H), 4.81 (m, 2H), 4.06 (m, 2H), 3.42 (s, 3H), 2.52 (m, 4H), 2.40 (m,2H), 1.92 (m, 4H).

Example 1244-(5-fluoro-2-methyl-3-((methylsulfonyl)methyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (300 MHz, chloroform-d) δ 8.36 (m, 1H), 7.81 (m, 1H), 7.48 (m,4H), 7.32 (m, 2H), 7.18 (m, 1H), 7.08 (m, 2H), 6.99 (m, 1H), 6.72 (m,1H), 4.92 (m, 2H), 4.41 (m, 2H), 4.16 (m, 2H), 2.92 (s, 3H), 2.51 (m,2H), 2.17 (s, 3H).

Example 1254-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-phenyl-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 126A (36 mg), phenylboronic acid (12.5 mg), K₂CO₃(1 M, 0.17 ml) and bis(triphenylphosphine)palladium(II) dichloride (7.2mg) in a mixture of 1,2-dimethoxyethane (2.2 ml), ethanol (0.6 ml) andwater (0.9 ml) was heated at 160° C. in a microwave reactor (CEMDiscover) for 10 minutes. The reaction mixture was acidified with adiluted trifluoroacetic acid methanol solution (3:1) and concentrated.The residue was suspended in a mixture of dimethyl sulfoxide andmethanol (1:1) and filtered. The filtrate was purified by RPHPLC (mobilephase: 10%400% acetonitrile in 0.1% TFA aqueous solution during 60 min)on a C18 column to provide the desired product. ¹H NMR (500 MHz,dimethyl sulfoxide-d₆) δ 8.26-8.31 (m, 1H), 7.82-7.94 (m, 1H), 7.69 (d,J=7.93 Hz, 1H), 7.50-7.58 (m, 2H), 7.46-7.49 (m, 1H), 7.41 (t, J=7.93Hz, 1H), 7.30 (dd, J=8.39, 7.17 Hz, 1H), 6.87-6.94 (m, 3H), 6.78-6.87(m, 7H), 6.72 (d, J=7.63 Hz, 1H), 4.76-5.00 (m, 2H), 4.25 (t, J=5.80 Hz,2H), 2.38-2.45 (m, 2H), 1.73 (s, 3H).

Example 1263-bromo-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid Example 126A methyl 4-o-tolyl-1H-indole-2-carboxylate

A mixture of 4-bromo-1H-indole (1.5 g) and o-tolylboronic acid (1.135 g)in dioxane (20 ml) was added tri-(t-butyl)phosphonium tetrafluoroborate(0.101 g), tris(dibenzylideneacetone)dipalladium(0) (0.159 g) and CsF(3.17 g). The reaction mixture was immediately purged with nitrogen, and2 ml of methanol was added. The resulting mixture was stirred at roomtemperature for 3 hours and concentrated. The residue was purified byflash chromatography, eluting with dichloromethane to provide thedesired product.

Example 126B methyl 3-bromo-4-o-tolyl-1H-indole-2-carboxylate

To a solution of EXAMPLE 126A (205 mg) in dichloromethane (5 ml) andtetrahydrofuran (5 ml) at 0° C. was added dropwise N-bromosuccinimide(144 mg) in tetrahydrofuran (3 ml). The mixture was stirred while theice bath slowly reached room temperature. The reaction mixture wasconcentrated and the residue was dissolved in dichloromethane andpurified by flash chromatography, eluting with 0-100% dichloromethane inhexane to provide the desired product.

Example 126C methyl3-bromo-1-(3-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indole-2-carboxylate

To a solution of EXAMPLE 126B (1.14 g) and 1-(3-bromopropoxy)naphthalene(0.922 g) in N,N-dimethylformamide (20 ml) was added cesium carbonate(2.158 g). The reaction was stirred at room temperature overnight anddiluted with ethyl acetate and washed with water. The organic layer wasdried over sodium sulfate, filtered and concentrated. The residue waspurified by flash chromatography, eluting with 0-50% dichloromethane inhexane to provide the title product.

Example 126D3-bromo-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 126C (22 mg), NaOH (0.167 ml), methanol (1.5 ml)and tetrahydrofuran (1.500 ml) was stirred at room temperature for 36hours, acidified with HCl and concentrated. The residue was purified byRPHPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFA aqueous solutionduring 60 minutes) on a C18 column to provide the title compound. ¹H NMR(500 MHz, dichloromethane-d₂) δ 8.30-8.40 (m, 1H), 7.79-7.85 (m, 1H),7.56 (d, J=8.54 Hz, 1H), 7.47-7.55 (m, 2H), 7.43 (d, J=8.24 Hz, 1H),7.35 (t, J=7.93 Hz, 1H), 7.28-7.33 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.18(m, 1H), 6.93 (d, J=7.02 Hz, 1H), 6.75 (d, J=7.63 Hz, 1H), 4.78-5.03 (m,2H), 4.16 (t, J=5.65 Hz, 2H), 2.37-2.54 (m, 2H), 2.01 (s, 3H).

Example 1284-(2-methylphenyl)-3-((4-methylphenyl)amino)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 13.20 (s, 1H), 8.21-8.32 (m,1H), 7.84-7.92 (m, 1H), 7.63 (d, J=8.54 Hz, 1H), 7.50-7.58 (m, 2H), 7.47(d, J=8.54 Hz, 1H), 7.39 (t, J=7.93 Hz, 1H), 7.19-7.29 (m, 1H),6.94-7.03 (m, 1H), 6.82-6.92 (m, 4H), 6.72 (d, J=7.02 Hz, 1H), 6.50-6.62(m, 3H), 5.98 (d, J=8.54 Hz, 2H), 4.66-5.08 (m, 2H), 4.19 (t, J=5.80 Hz,2H), 2.31-2.42 (m, 2H), 2.06 (s, 3H), 1.86 (s, 3H).

Example 1293-(4-hydroxyphenyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.71 (s, 1H), 8.91 (s, 1H),8.24-8.37 (m, 1H), 7.86-7.92 (m, 1H), 7.66 (d, J=8.24 Hz, 1H), 7.50-7.60(m, 2H), 7.44-7.50 (m, 1H), 7.40 (t, J=7.93 Hz, 1H), 7.27 (dd, J=8.54,7.02 Hz, 1H), 6.81-7.01 (m, 4H), 6.77 (d, J=7.32 Hz, 2H), 6.59 (d,J=7.63 Hz, 2H), 6.22 (d, J=8.24 Hz, 2H), 4.61-5.08 (m, 2H), 4.24 (t,J=5.80 Hz, 2H), 2.27-2.44 (m, 2H), 1.73 (s, 3H).

Example 1303-(3-hydroxyphenyl)-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.79 (s, 1H), 8.79 (s, 1H),8.14-8.47 (m, 1H), 7.83-7.92 (m, 1H), 7.67 (d, J=8.24 Hz, 1H), 7.51-7.59(m, 2H), 7.45-7.50 (m, 1H), 7.41 (t, J=7.93 Hz, 1H), 7.28 (dd, J=8.24,7.02 Hz, 1H), 6.89-6.95 (m, 2H), 6.75-6.87 (m, 4H), 6.53-6.61 (m, 1H),6.27-6.33 (m, 2H), 6.18 (d, J=7.32 Hz, 1H), 4.67-5.03 (m, 2H), 4.24 (t,J=5.80 Hz, 2H), 2.28-2.42 (m, 2H), 1.79 (s, 3H).

Example 1314-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-pyridin-4-yl-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 13.49 (s, br, 2H), 8.30 (d,J=6.10 Hz, 2H), 8.25 (d, J=7.93 Hz, 1H), 7.88 (d, J=7.63 Hz, 1H), 7.82(d, J=8.54 Hz, 1H), 7.45-7.58 (m, 3H), 7.37-7.44 (m, 2H), 7.34 (d,J=5.19 Hz, 2H), 6.97-7.04 (m, 1H), 6.84-6.97 (m, 4H), 6.80 (d, J=7.63Hz, 1H), 4.82-5.09 (m, 2H), 4.28 (t, J=5.65 Hz, 2H), 2.39-2.48 (m, 2H),1.77 (s, 3H).

Example 1324-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-pyridin-3-yl-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 13.27 (s, 1H), 8.41 (d, J=5.19Hz, 2H), 8.21-8.32 (m, 1H), 7.78-7.92 (m, 3H), 7.50-7.59 (m, 2H),7.47-7.50 (m, 1H), 7.37-7.44 (m, 3H), 6.95-7.02 (m, 1H), 6.88-6.95 (m,4H), 6.80 (d, J=7.63 Hz, 1H), 4.83-5.19 (m, 2H), 4.28 (t, J=5.80 Hz,2H), 2.40-2.48 (m, 2H), 1.75 (s, 3H), J=5.80 Hz, 2H), 2.41-2.48 (m, 2H),1.75 (s, 1H).

Example 1333-cyano-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid Example 133A methyl3-cyano-1-(3-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indole-2-carboxylate

A mixture of EXAMPLE 126C (100 mg), dicyanozinc (222 mg) and Pd(PPh₃)₄(21.87 mg, 0.019 mmol) in N,N-dimethylformamide (4 ml) was heated at180° C. for 400 seconds in a microwave reactor (CEM Discover) and thenconcentrated. The residue was dissolved in dichloromethane and purifiedby flash chromatography, eluting with 50%-100% dichloromethane in hexaneto provide the desired product.

Example 133B3-cyano-4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 133A (16 mg) and sodium hydroxide (200 μl) intetrahydrofuran (0.5 ml) and methanol (0.5 ml) was stirred overnight,neutralized with diluted HCl, and concentrated. The residue was purifiedby RPHPLC to provide the desired product. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 14.24 (s, 1H), 8.14 (d, J=8.54 Hz, 1H), 7.86 (dd,J=7.48, 5.65 Hz, 2H), 7.35-7.61 (m, 5H), 7.18-7.36 (m, 3H), 7.12 (d,J=7.32 Hz, 1H), 7.06 (d, J=7.02 Hz, 1H), 6.89 (d, J=7.32 Hz, 1H),4.77-5.18 (m, 2H), 4.24 (t, J=5.03 Hz, 2H), 2.30-2.47 (m, 2H), 1.99 (s,3H).

Example 1343-bromo-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acidExample 134A ethyl 3-bromo-5-fluoro-1H-indole-2-carboxylate

The title compound was prepared by substituting EXAMPLE 126A with ethyl5-fluoro-1H-indole-2-carboxylate in EXAMPLE 126B.

Example 134B

To a solution of EXAMPLE 134A (465 mg) and 1-(3-bromopropoxy)naphthalene(431 mg) in N,N-dimethylformamide (10 ml) was added cesium carbonate(1059 mg). The reaction was stirred at room temperature overnight anddiluted with ethyl acetate, and washed with water. The organic layer wasdried over sodium sulfate, filtered, and concentrated. The residue waspurified by RPHPLC to provide ethyl3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate.This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran andmethanol to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-D₆) δ 8.13 (d, J=7.98 Hz, 1H), 7.85 (d, J=7.67 Hz, 1H), 7.74(dd, J=9.21, 4.30 Hz, 1H), 7.42-7.58 (m, 3H), 7.37 (t, J=7.98 Hz, 1H),7.27 (dd, J=8.90, 2.45 Hz, 1H), 7.10-7.20 (m, 1H), 6.85 (d, J=7.36 Hz,1H), 4.87 (t, J=6.90 Hz, 2H), 4.14 (t, J=5.83 Hz, 2H), 2.21-2.39 (m,2H).

Example 1355-(benzyloxy)-1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid Example 135A ethyl 5-(benzyloxy)-3-bromo-1H-indole-2-carboxylate

The title compound was prepared by substituting EXAMPLE 126A with ethyl5-(benzyloxy)-1H-indole-2-carboxylate in EXAMPLE 126B.

Example 135B ethyl5-(benzyloxy)-3-bromo-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

To a solution of EXAMPLE 135A (500 mg) and 1-(3-bromopropoxy)naphthalene(354 mg) in N,N-dimethylformamide (10 ml) was added Cs₂CO₃ (871 mg). Thereaction was stirred at room temperature overnight, diluted with ethylacetate and washed with water. The organic layer was dried over sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography, eluting with 0%-50% dichloromethane in hexane, toprovide the desired product.

Example 135C5-(benzyloxy)-1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 135B (30 mg), 2-(trifluoromethyl)phenylboronic acid(15.3 mg), tetrakis(triphenylphosphine)palladium(0) (3.1 mg) and cesiumfluoride (16.3 mg) in dimethoxyethane (1.4 ml) and methanol (0.7 ml) washeated at 100° C. in a microwave reactor (CEM Discover) for 30 minutesand was concentrated. The residue was purified by flash chromatography,eluting with 0%-100% dichloromethane in hexane, to provide ethyl5-(benzyloxy)-1-(3-(naphthalen-1-yloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate.This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran andmethanol to provide the title compound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 12.67 (s, 1H), 8.04-8.40 (m, 1H), 7.87 (d, J=7.32 Hz,1H), 7.82 (d, J=7.63 Hz, 1H), 7.69 (t, J=7.32 Hz, 1H), 7.57-7.65 (m,2H), 7.44-7.56 (m, 3H), 7.26-7.41 (m, 7H), 6.97 (dd, J=9.00, 2.29 Hz,1H), 6.85 (d, J=7.93 Hz, 1H), 6.55 (d, J=2.14 Hz, 1H), 4.83-4.98 (m,4H), 4.05-4.24 (m, 2H), 2.28-2.40 (m, 2H).

Example 1365-fluoro-3-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.87 (s, 1H), 8.17 (d, J=8.24Hz, 1H), 7.86 (d, J=7.93 Hz, 1H), 7.74 (dd, J=9.15, 4.27 Hz, 1H),7.42-7.57 (m, 3H), 7.38 (t, J=7.93 Hz, 1H), 7.24-7.32 (m, 2H), 7.22 (t,J=7.32 Hz, 1H), 7.07-7.15 (m, 2H), 6.87 (d, J=7.32 Hz, 1H), 6.75 (dd,J=9.31, 2.59 Hz, 1H), 4.77-5.03 (m, 2H), 4.18 (t, J=5.80 Hz, 2H),2.28-2.43 (m, 2H), 2.01 (s, 3H).

Example 137 5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 13.08 (s, 1H), 8.21 (d, J=7.93Hz, 1H), 7.86 (d, J=7.63 Hz, 1H), 7.65 (dd, J=9.00, 4.12 Hz, 1H),7.47-7.58 (m, 2H), 7.41-7.48 (m, 2H), 7.37 (t, J=7.78 Hz, 1H), 7.24 (s,1H), 7.01-7.11 (m, 1H), 6.85 (d, J=7.32 Hz, 1H), 4.88 (t, J=6.87 Hz,2H), 4.13 (t, J=5.49 Hz, 2H), 2.21-2.37 (m, 2H).

Example 1385-fluoro-1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.89 (s, 1H), 8.19 (d, J=8.24Hz, 1H), 7.87 (d, J=7.93 Hz, 1H), 7.82 (d, J=7.63 Hz, 1H), 7.75 (dd,J=9.15, 4.27 Hz, 1H), 7.69 (t, J=7.48 Hz, 1H), 7.61 (t, J=7.63 Hz, 1H),7.43-7.57 (m, 3H), 7.38 (t, J=7.93 Hz, 1H), 7.34 (d, J=7.63 Hz, 1H),7.07-7.16 (m, 1H), 6.85 (d, J=7.63 Hz, 1H), 6.73 (dd, J=9.31, 2.29 Hz,1H), 4.72-5.16 (m, 2H), 4.06-4.28 (m, 2H), 2.27-2.42 (m, 2H).

Example 1395-fluoro-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.81 (s, 1H), 8.14 (d, J=8.24Hz, 1H), 7.86 (d, J=7.93 Hz, 1H), 7.74 (dd, J=9.15, 4.27 Hz, 1H),7.50-7.55 (m, 1H), 7.44-7.50 (m, 2H), 7.32-7.42 (m, 3H), 7.16-7.22 (m,1H), 7.09-7.15 (m, 1H), 7.03-7.07 (m, 1H), 6.86 (d, J=7.63 Hz, 1H), 6.70(dd, J=9.15, 2.44 Hz, 1H), 4.72-5.06 (m, 2H), 4.17 (t, J=5.80 Hz, 2H),2.58-2.78 (m, 1H), 2.24-2.43 (m, 2H), 1.01 (d, J=6.71 Hz, 3H), 0.94 (d,J=7.02 Hz, 3H).

Example 1404-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-3-((3-(trifluoromethoxy)phenyl)amino)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 13.09 (s, 1H), 8.20-8.35 (m,1H), 7.81-7.92 (m, 1H), 7.67 (d, J=8.54 Hz, 1H), 7.50-7.58 (m, 2H), 7.47(d, J=8.24 Hz, 1H), 7.39 (t, J=7.93 Hz, 1H), 7.27 (dd, J=8.39, 7.17 Hz,1H), 7.10 (s, 1H), 6.82-6.98 (m, 4H), 6.74-6.82 (m, 3H), 6.30 (d, J=8.24Hz, 1H), 5.96 (d, J=7.93 Hz, 1H), 5.90 (s, 1H), 4.78-5.01 (m, 2H), 4.19(t, J=5.80 Hz, 2H), 2.31-2.44 (m, 2H), 1.89 (s, 3H).

Example 1415-(benzyloxy)-1-(3-(1-naphthyloxy)propyl)-3-((3-(trifluoromethoxy)phenyl)amino)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.22 (d, J=7.67 Hz, 1H), 8.04(s, 1H), 7.86 (dd, J=7.21, 1.69 Hz, 1H), 7.57 (d, J=8.90 Hz, 1H),7.48-7.55 (m, 2H), 7.43-7.47 (m, 1H), 7.28-7.41 (m, 6H), 7.17 (t, J=8.13Hz, 1H), 6.92-6.99 (m, 1H), 6.84 (d, J=7.67 Hz, 1H), 6.76 (d, J=2.45 Hz,1H), 6.64-6.72 (m, 2H), 6.61 (d, J=6.14 Hz, 1H), 4.94 (s, 2H), 4.78-4.86(m, 2H), 4.13 (t, J=5.98 Hz, 1H), 2.24-2.35 (m, 2H).

Example 1425-(benzyloxy)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.23 (d, J=8.29 Hz, 1H), 7.86(d, J=7.06 Hz, 1H), 7.49-7.58 (m, 3H), 7.42-7.48 (m, 3H), 7.39 (t,J=7.06 Hz, 3H), 7.29-7.36 (m, 1H), 7.23 (d, J=2.15 Hz, 1H), 7.14 (s,1H), 6.91 (dd, J=8.90, 2.46 Hz, 1H), 6.84 (d, J=7.98 Hz, 1H), 5.08 (s,2H), 4.83 (t, J=6.60 Hz, 2H), 4.12 (t, J=6.29 Hz, 2H), 2.27-2.34 (m,2H).

Example 1435-(benzyloxy)-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.19 (d, J=7.98 Hz, 1H), 7.86(d, J=7.36 Hz, 1H), 7.60 (d, J=9.51 Hz, 1H), 7.43-7.56 (m, 3H),7.25-7.43 (m, 8H), 7.13-7.21 (m, 1H), 7.04 (d, J=6.75 Hz, 1H), 6.98 (dd,J=9.21, 2.45 Hz, 1H), 6.85 (d, J=7.36 Hz, 1H), 6.53 (d, J=2.15 Hz, 1H),4.74-5.06 (m, 4H), 4.16 (t, J=5.68 Hz, 2H), 2.64-2.81 (m, 1H), 2.27-2.42(m, 2H), 1.00 (d, J=7.06 Hz, 3H), 0.92 (d, J=6.75 Hz, 3H).

Example 1443-(2-(te-butoxymethyl)phenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.22 (d, J=7.67 Hz, 1H), 7.86(d, J=7.67 Hz, 1H), 7.70 (dd, J=9.05, 4.14 Hz, 1H), 7.43-7.57 (m, 4H),7.26-7.41 (m, 3H), 7.15 (dd, J=7.36, 1.23 Hz, 1H), 7.05-7.12 (m, 1H),6.85 (d, J=7.36 Hz, 1H), 6.77 (dd, J=9.51, 2.45 Hz, 1H), 4.77-5.04 (m,2H), 4.17 (t, J=5.68 Hz, 2H), 4.11 (q, J=10.74 Hz, 2H), 2.28-2.42 (m,2H), 0.75-0.88 (m, 9H).

Example 1455-fluoro-1-(3-(1-naphthyloxy)propyl)-3-(2-((3-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.17 (d, J=7.98 Hz, 1H), 7.85(d, J=7.36 Hz, 1H), 7.66 (dd, J=9.21, 4.30 Hz, 1H), 7.38-7.60 (m, 6H),7.21-7.37 (m, 3H), 7.12 (d, J=7.98 Hz, 1H), 7.03-7.11 (m, 1H), 6.92 (dd,J=8.13, 1.99 Hz, 1H), 6.75-6.83 (m, 3H), 4.73-5.00 (m, 4H), 3.96-4.15(m, J=6.44 Hz, 2H), 2.17-2.29 (m, 2H).

Example 1465-chloro-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.10 (d, J=8.29 Hz, 1H), 7.86(d, J=7.67 Hz, 1H), 7.75 (d, J=8.90 Hz, 1H), 7.52 (t, J=6.90 Hz, 1H),7.43-7.49 (m, 2H), 7.32-7.42 (m, 3H), 7.25 (dd, J=8.90, 1.84 Hz, 1H),7.15-7.22 (m, 1H), 7.04 (d, J=6.75 Hz, 1H), 6.98 (d, J=1.84 Hz, 1H),6.85 (d, J=7.36 Hz, 1H), 4.92 (t, J=7.36 Hz, 2H), 4.17 (t, J=5.83 Hz,2H), 2.59-2.74 (m, 1H), 2.30-2.44 (m, 2H), 1.01 (d, J=6.75 Hz, 3H), 0.92(d, J=7.06 Hz, 3H).

Example 1475-chloro-3-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.13 (d, J=8.59 Hz, 1H), 7.86(d, J=8.59 Hz, 1H), 7.74 (d, J=8.90 Hz, 1H), 7.42-7.58 (m, 3H), 7.38 (t,J=7.98 Hz, 1H), 7.17-7.34 (m, 4H), 7.12 (d, J=7.06 Hz, 1H), 7.02 (d,J=1.84 Hz, 1H), 6.87 (d, J=7.36 Hz, 1H), 4.75-5.01 (m, 2H), 4.18 (t,J=5.83 Hz, 2H), 2.32-2.43 (m, 2H), 1.99 (s, 3H).

Example 1485-hydroxy-3-(2-isopropylphenyl)-1-(3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.84 (s, 1H), 7.35-7.46 (m,2H), 7.32 (t, J=6.75 Hz, 1H), 7.13-7.21 (m, 1H), 7.04 (d, J=7.98 Hz,1H), 6.98 (t, J=8.13 Hz, 1H), 6.80 (d, J=7.67 Hz, 1H), 6.63 (d, J=8.29Hz, 1H), 6.59 (d, J=8.29 Hz, 1H), 6.37 (d, J=2.15 Hz, 1H), 4.72 (t,J=7.36 Hz, 2H), 3.92 (t, J=5.98 Hz, 2H), 2.65-2.73 (m, 2H), 2.57-2.64(m, 2H), 2.14-2.25 (m, 2H), 1.64-1.78 (m, 4H), 1.04 (d, J=6.75 Hz, 3H),0.98 (d, J=6.75 Hz, 3H).

Example 1495-hydroxy-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid Example 149A ethyl5-(benzyloxy)-3-(2-isopropylphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

The title compound was prepared according to the procedure for EXAMPLE135C by substituting 2-(isopropyl)phenylboronic acid for2-(trifluoromethyl)phenylboronic acid.

Example 149B ethyl5-hydroxy-3-(2-isopropylphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

A mixture of EXAMPLE 149A (250 mg) and dihydroxypalladium (on carbon)(20 mg) in tetrahydrofuran was stirred a room temperature under ahydrogen atmosphere (30 psi) for 29 hours. The insoluble material wasfiltered off and the filtrate was concentrated. The residue was purifiedby flash chromatography, eluting with dichloromethane to provide thetitle compound.

Example 149C5-hydroxy-3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

To a solution of EXAMPLE 149B (22 mg) in tetrahydrofuran (2 ml) andmethanol (2 ml) was added 10% NaOH 0.3 ml. The reaction was heated at70° C. for 24 hours, cooled, acidified with diluted aqueousHCl andconcentrated. The residue was purified by RPHPLC to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.83 (s, 1H),8.20-8.23 (m, 1H), 7.85-7.88 (m, 1H), 7.45-7.55 (m, 5H), 7.34-7.40 (m,2H), 7.28-7.34 (m, 1H), 7.17 (td, J=7.36, 1.23 Hz, 1H), 7.04 (dd,J=7.52, 1.38 Hz, 1H), 6.85 (d, J=7.36 Hz, 1H), 6.75 (dd, J=8.90, 2.45Hz, 1H), 6.37 (d, J=2.15 Hz, 1H), 4.84 (t, J=7.52 Hz, 2H), 4.15 (t,J=5.68 Hz, 2H), 2.63-2.87 (m, 1H), 2.25-2.41 (m, 2H), 1.02 (d, J=6.75Hz, 3H), 0.96 (d, J=7.06 Hz, 3H).

Example 1503-(2-isopropylphenyl)-5-(4-morpholin-4-ylbutoxy)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 149A (36 mg), 1-chloro-4-iodobutane (0.043 ml) andcesium carbonate (116 mg) in N,N-dimethylformamide (2 ml) was stirred atroom temperature overnight. The inorganic salt was filtered off. To theN,N-dimethylformamide solution was added morpholine (0.2 ml) and theresulting mixture was heated at 60° C. for 5 hours. The reaction mixturewas concentrated and the residue was purified by RPHPLC (mobile phase:10%-100% acetonitrile in 0.1% TFA aqueous solution during 60 min) on aC18 column to give ethyl3-(2-isopropylphenyl)-5-(4-morpholinobutoxy)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate.This ester was hydrolyzed with aqueous NaOH in a mixture oftetrahydrofuran and methanol to provide the title compound. ¹H NMR (400MHz, dimethyl sulfoxide-d₆) δ 9.52 (s, 1H), 8.20 (d, J=8.29 Hz, 1H),7.87 (d, J=7.98 Hz, 1H), 7.59 (d, J=8.90 Hz, 1H), 7.43-7.57 (m, 3H),7.30-7.43 (m, 3H), 7.14-7.23 (m, 1H), 7.06 (d, J=7.36 Hz, 1H), 6.89 (dd,J=9.05, 2.30 Hz, 1H), 6.85 (d, J=7.67 Hz, 1H), 6.43 (d, J=2.45 Hz, 1H),4.88 (t, J=7.21 Hz, 2H), 4.15 (t, J=5.83 Hz, 2H), 3.89-4.03 (m, J=11.97Hz, 2H), 3.75-3.89 (m, 2H), 3.55-3.70 (m, 2H), 3.07-3.17 (m, 2H), 3.02(s, br, 2H), 2.61-2.78 (m, 2H), 2.23-2.45 (m, 2H), 1.60-1.85 (m, 4H).

Example 151 5-fluoro-1-(3-(1-naphthyloxy)propyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

A mixture of1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(43.2 mg), ethyl3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate(The synthesis of this compound was described in EXAMPLE 134B as anintermediate) (43 mg),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (15.01 mg) and K₃PO₄(58.2 mg) in toluene (2.1 ml) was heated in a microwave reactor (CEMDiscover) at 110° C. for 2 hours. The reaction was directly loaded intoa silica cartridge, and eluted with 0%-25% ethyl acetate indichloromethane. The collected desired ester was hydrolized with NaOH intetrahydrofuran-methanol-H₂O at 50° C. overnight to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.15 (d, J=8.90 Hz,1H), 7.86 (d, J=7.36 Hz, 1H), 7.71 (dd, J=9.21, 4.30 Hz, 1H), 7.42-7.56(m, 3H), 7.32-7.41 (m, 1H), 7.05-7.16 (m, 1H), 6.92 (dd, J=9.36, 2.61Hz, 1H), 6.86 (d, J=7.36 Hz, 1H), 4.69-5.00 (m, 2H), 4.17 (t, J=5.83 Hz,2H), 3.72 (s, 3H), 2.27-2.43 (m, 2H), 1.99 (s, 3H), 1.90 (s, 3H).

Example 1523-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-5-phenyl-1H-indole-2-carboxylicacid

A mixture of ethyl5-chloro-3-(2-isopropylphenyl)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate(the synthesis of this compound was similar to the intermediatedescribed in EXAMPLE 134) (56 mg), phenylboronic acid (26 mg),diacetoxypalladium (2.39 mg),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (8.74 mg) and K₃PO₄(67.8 mg) was heated at 180° C. in a CEM microwave synthesizer for 1hour. The reaction was concentrated and the residue was purified byflash chromatography, eluting with 0-50% dichloromethane in hexane. Thecollected desired ester was saponified with NaOH intetrahydrofuran-methanol-H₂O at 50° C. overnight to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 12.76 (s, 1H), 8.17(d, J=8.29 Hz, 1H), 7.86 (d, J=7.67 Hz, 1H), 7.78 (d, J=8.90 Hz, 1H),7.43-7.58 (m, 6H), 7.32-7.44 (m, 5H), 7.28 (t, J=7.21 Hz, 1H), 7.22 (d,J=1.84 Hz, 1H), 7.16-7.21 (m, 1H), 7.06-7.12 (m, 1H), 6.87 (d, J=7.36Hz, 1H), 4.95 (t, J=7.06 Hz, 2H), 4.21 (t, J=6.14 Hz, 2H), 2.68-2.82 (m,J=7.06 Hz, 1H), 2.37-2.47 (m, 2H), 1.03 (d, J=6.75 Hz, 3H), 0.96 (d,J=6.75 Hz, 3H).

Example 1533-(2,6-dimethylphenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 12.72 (s, 1H), 8.19 (d, J=7.98Hz, 1H), 7.86 (d, J=7.36 Hz, 1H), 7.74 (dd, J=9.21, 4.30 Hz, 1H),7.42-7.56 (m, 3H), 7.37 (t, J=7.98 Hz, 1H), 7.05-7.20 (m, 4H), 6.84 (d,J=7.67 Hz, 1H), 6.62 (dd, J=9.05, 2.61 Hz, 1H), 4.93 (t, J=6.90 Hz, 2H),4.14 (t, J=5.98 Hz, 2H), 2.26-2.44 (m, 2H), 1.87 (s, 6H).

Example 1543-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.20 (d, J=7.98 Hz, 1H),7.83-7.91 (m, 1H), 7.67 (d, J=8.29 Hz, 1H), 7.43-7.57 (m, 3H), 7.30-7.42(m, 3H), 7.22-7.28 (m, 1H), 7.13-7.22 (m, 1H), 6.98-7.11 (m, 3H), 6.86(d, J=7.36 Hz, 1H), 4.83-4.97 (m, 2H), 4.18 (t, J=5.98 Hz, 2H),2.62-2.75 (m, 1H), 2.29-2.43 (m, 2H), 1.02 (d, J=6.75 Hz, 3H), 0.94 (d,J=7.06 Hz, 3H).

Example 1551-(3-(1-naphthyloxy)propyl)-5-((1E)-pent-1-enyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.94 (s, 1H), 8.24 (d, J=7.93Hz, 1H), 7.87 (d, J=7.63 Hz, 1H), 7.60 (s, 1H), 7.48-7.56 (m, 3H), 7.46(d, J=8.24 Hz, 1H), 7.37 (t, J=7.93 Hz, 1H), 7.32 (dd, J=8.85, 1.22 Hz,1H), 7.20 (s, 1H), 6.85 (d, J=7.63 Hz, 1H), 6.44 (d, J=15.87 Hz, 1H),6.12-6.25 (m, 1H), 4.85 (t, J=6.87 Hz, 2H), 4.13 (t, J=5.80 Hz, 2H),2.26-2.35 (m, 2H), 2.09-2.21 (m, 2H), 1.38-1.53 (m, 2H), 0.92 (t, J=7.32Hz, 3H).

Example 1563-(2,6-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 12.59 (s, 1H), 8.21-8.27 (m,1H), 7.83-7.89 (m, 1H), 7.68 (d, J=8.59 Hz, 1H), 7.42-7.57 (m, 3H), 7.37(t, J=7.82 Hz, 1H), 7.20-7.27 (m, 1H), 7.07-7.18 (m, 3H), 6.94-7.05 (m,2H), 6.84 (d, J=7.67 Hz, 1H), 4.94 (t, J=7.06 Hz, 2H), 4.15 (t, J=5.83Hz, 2H), 2.32-2.43 (m, 2H), 1.88 (s, 6H).

Example 1571-(3-(1-naphthyloxy)propyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.20 (d, J=7.98 Hz, 1H), 7.86(d, J=7.98 Hz, 1H), 7.66 (d, J=8.90 Hz, 1H), 7.42-7.56 (m, 3H),7.33-7.40 (m, 1H), 7.20-7.28 (m, 2H), 7.07 (t, J=7.52 Hz, 1H), 6.86 (d,J=7.67 Hz, 1H), 4.73-5.02 (m, 2H), 4.18 (t, J=5.83 Hz, 2H), 3.74 (s,3H), 2.30-2.44 (m, 2H), 2.01 (s, 3H), 1.92 (s, 3H).

Example 1583-(2-chlorophenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 13.00 (s, 1H), 8.18 (d, J=7.98Hz, 1H), 7.86 (d, J=7.36 Hz, 1H), 7.75 (dd, J=9.05, 4.14 Hz, 1H),7.43-7.59 (m, 4H), 7.31-7.43 (m, 4H), 7.06-7.17 (m, 1H), 6.78-6.92 (m,2H), 4.64-5.21 (m, 2H), 4.19 (t, J=5.83 Hz, 2H), 2.26-2.42 (m, 2H).

Example 1593-((1E)-5-(dimethylamino)pent-1-enyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid Example 159A (E)-ethyl3-(5-chloropent-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

A mixture of ethyl3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate(The synthesis of this compound was described in EXAMPLE 134B as anintermediate) (404 mg),(E)-2-(5-chloropent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.394 ml), diacetoxypalladium (19.28 mg),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (70.5 mg) and K₃PO₄(547 mg) was heated in a microwave reactor (CEM Discover) at 100° C. for1 hour. The insoluble material was removed by filtration and thefiltrate was concentrated. The residue was purified by flashchromatography, eluting with dichloromethane to provide the titlecompound.

Example 159B

Example 159A (100 mg) in tetrahydrofuran (1 ml) was mixed with 1 Mdimethylamine in methanol (10 ml) and the resulting solution was heated50° C. for 3 days and concentrated. The residue was dissolved intetrahydrofuran and methanol. 3 ml of 10% aqueous NaOH was added. Themixture was heated at 50° C. overnight and was concentrated. The residuewas purified by RPHPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFAaqueous solution during 60 min) on a C18 column to provide the titlecompound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 13.56 (s, br, 1H),9.39 (s, br, 1H), 8.19 (d, J=7.93 Hz, 1H), 7.87 (d, J=7.93 Hz, 1H),7.64-7.73 (m, 2H), 7.43-7.59 (m, 3H), 7.38 (t, J=7.93 Hz, 1H), 7.04-7.18(m, 2H), 6.85 (d, J=7.32 Hz, 1H), 6.17-6.31 (m, 1H), 4.82 (t, J=7.02 Hz,2H), 4.14 (t, J=5.80 Hz, 2H), 3.06-3.16 (m, 2H), 2.80 (d, J=4.58 Hz,6H), 2.22-2.35 (m, 4H), 1.78-1.90 (m, 2H).

Example 1603-((1E)-6-((2-carboxybenzoyl)amino)hex-1-enyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid Example 160A

(E)-ethyl3-(6-chlorohex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

The title compound was prepared by substituting(E)-2-(6-chlorohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for(E)-2-(5-chloropent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane inEXAMPLE 159A.

Example 160B3-((1E)-6-((2-carboxybenzoyl)amino)hex-1-enyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 160A (531 mg) and potassium1,3-dioxoisoindolin-2-ide (213 mg) in N,N-dimethylformamide (10 ml) washeated at 80° C. for 8 hours. The reaction was diluted with ethylacetate and washed with water. The organic layer was dried over sodiumsulfate and was concentrated. The residue was purified by flashchromatography, eluting with 0-100% ethyl acetate in dichloromethane togive (E)-ethyl3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate.This ester was dissolved in a mixture of tetrahydrofuran and methanoland 5 equivalents of aqueous NaOH (10%) was added. The mixture washeated at 50° C. for 5 hours. The reaction mixture was concentrated andthe residue was dissolved in dimethyl sulfoxide and trifluoroaceticacid-methanol (3:1), and purified by RPHPLC to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 13.06 (s, 2H), 8.25(t, J=5.52 Hz, 1H), 8.19 (dd, J=7.83, 1.38 Hz, 1H), 7.86 (dd, J=7.21,1.99 Hz, 1H), 7.74 (dd, J=7.52, 1.38 Hz, 1H), 7.60-7.69 (m, 2H),7.43-7.58 (m, 5H), 7.34-7.41 (m, 2H), 6.99-7.16 (m, 2H), 6.85 (d, J=7.36Hz, 1H), 6.15-6.32 (m, 1H), 4.65-4.96 (m, 2H), 4.13 (t, J=5.68 Hz, 2H),3.20-3.29 (m, 2H), 2.20-2.36 (m, 4H), 1.49-1.67 (m, 4H).

Example 1613-((1E)-6-aminohex-1-enyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

(E)-ethyl3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate(The synthesis of this compound was described in EXAMPLE 160B as anintermediate.) was dissolved in a mixture of tetrahydrofuran andmethanol and 5 equivalents of aqueous NaOH (10%) was added. The mixturewas heated at 50° C. for 2 days. The reaction mixture was concentratedand the residue was purified by reverse phaseHPLC (mobile phase: 0-100%acetonitrile in 0.1% TFA aqueous solution during 60 min) on a C18 columnto provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ8.18 (d, J=9.21 Hz, 1H), 7.82-7.89 (m, 1H), 7.57-7.70 (m, 4H), 7.42-7.55(m, 4H), 7.37 (t, J=7.67 Hz, 1H), 7.01-7.14 (m, 2H), 6.84 (d, J=7.67 Hz,1H), 6.14-6.29 (m, 1H), 4.80 (t, J=7.83 Hz, 2H), 4.13 (t, J=5.68 Hz,2H), 2.70-2.97 (m, 2H), 2.11-2.37 (m, 4H), 1.41-1.76 (m, 4H).

Example 1623-(6-aminohexyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

A mixture of (E)-ethyl3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate(The synthesis of this compound was described in EXAMPLE 160B as anintermediate.) (270 mg) and hydrazine (0.030 ml) in tetrahydrofuran(1.00 ml) and ethanol (3 ml) was heated at 50° C. overnight andconcentrated. The residue was dissolved in tetrahydrofuran and methanoland then aqueous 10% NaOH was added. The resulting was heated at 50° C.overnight and concentrated. The residue was purified by RPHPLC toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ8.17 (dd, J=8.44, 1.07 Hz, 1H), 7.84-7.89 (m, 1H), 7.60 (dd, J=9.21,4.30 Hz, 1H), 7.41-7.56 (m, 4H), 7.32-7.40 (m, 1H), 7.01-7.11 (m, 1H),6.84 (d, J=7.06 Hz, 1H), 4.80 (t, J=7.21 Hz, 2H), 4.12 (t, J=5.83 Hz,2H), 2.94-3.06 (m, 2H), 2.75 (t, J=8.29 Hz, 2H), 2.20-2.35 (m, 2H),1.43-1.63 (m, 4H), 1.27-1.36 (m, 4H).

Example 1633-(5-(dimethylamino)pentyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

A mixture of EXAMPLE 159 (45 mg) and Pt/C (5%) (10 mg) intetrahydrofuran (2 ml) was stirred under hydrogen (30 psi) at roomtemperature for 2.5 hours. The insoluble material was filtered off andthe filtrate was concentrated. The residue was purified by RPHPLC toprovide the desired product. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ9.28 (s, 1H), 8.17 (d, J=7.67 Hz, 1H), 7.81-7.91 (m, 1H), 7.61 (dd,J=9.21, 4.30 Hz, 1H), 7.43-7.56 (m, 4H), 7.37 (t, J=7.82 Hz, 1H),7.01-7.10 (m, 1H), 6.84 (d, J=7.36 Hz, 1H), 4.80 (t, J=6.90 Hz, 2H),4.12 (t, J=5.83 Hz, 2H), 2.91-3.07 (m, 4H), 2.19-2.35 (m, 2H), 1.50-1.69(m, 4H), 1.25-1.39 (m, 2H).

Example 164 6-chloro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.23-8.27 (m, 1H), 7.83-7.87(m, 1H), 7.71 (s, 1H), 7.67 (d, J=8.29 Hz, 1H), 7.43-7.54 (m, 3H), 7.36(t, J=7.98 Hz, 1H), 7.27 (s, 1H), 7.06 (dd, J=8.59, 1.53 Hz, 1H), 6.84(d, J=7.36 Hz, 1H), 4.84 (t, J=6.90 Hz, 2H), 4.11 (t, J=5.68 Hz, 2H),2.27-2.33 (m, 2H).

Example 1653-(2-((1E)-5-(dimethylamino)pent-1-enyl)phenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.90 (s, 1H), 9.20 (s, 1H),8.16 (d, J=8.24 Hz, 1H), 7.87 (d, J=7.93 Hz, 1H), 7.72-7.80 (m, 1H),7.67 (d, J=7.63 Hz, 1H), 7.50-7.56 (m, 1H), 7.45-7.50 (m, 2H), 7.22-7.41(m, 3H), 7.10-7.19 (m, 2H), 6.88 (d, J=7.63 Hz, 1H), 6.77 (dd, J=9.46,2.44 Hz, 1H), 6.04-6.21 (m, 2H), 4.90-5.00 (m, 1H), 4.82-4.91 (m, 1H),4.20 (t, J=5.80 Hz, 2H), 2.83-2.92 (m, 2H), 2.63-2.72 (m, 6H), 2.34-2.41(m, 2H), 1.97 (q, J=6.61 Hz, 2H), 1.55-1.65 (m, 2H).

Example 1663-(2-(dimethylamino)phenyl)-5-fluoro-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid

¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.18 (d, J=7.98 Hz, 1H),7.84-7.88 (m, 1H), 7.74 (dd, J=8.90, 4.30 Hz, 1H), 7.42-7.56 (m, 5H),7.34-7.41 (m, 1H), 7.19-7.25 (m, 2H), 7.09-7.15 (m, 1H), 6.95 (dd,J=9.21, 2.45 Hz, 1H), 6.87 (d, J=7.06 Hz, 1H), 4.87 (t, J=7.06 Hz, 2H),4.19 (t, J=5.98 Hz, 2H), 2.63 (s, 6H), 2.33-2.42 (m, 2H).

Example 167 1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid

¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ 12.96 (s, 1H), 8.06-8.44 (m,1H), 7.82-7.90 (m, 1H), 7.68 (d, J=7.93 Hz, 1H), 7.60 (d, J=8.54 Hz,1H), 7.50-7.55 (m, 2H), 7.46 (d, J=8.24 Hz, 1H), 7.37 (t, J=7.93 Hz,1H), 7.28 (s, 1H), 7.19 (t, J=7.63 Hz, 1H), 7.09 (t, J=7.48 Hz, 1H),6.84 (d, J=7.63 Hz, 1H), 4.88 (t, J=7.02 Hz, 2H), 4.13 (t, J=5.80 Hz,2H), 2.27-2.37 (m, 2H).

Example 1681-methyl-5-(4-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indol-2-yl)-1H-pyrazol-3-olExample 1681-methyl-5-(4-(2-methylphenyl)-1-[3-(1-naphthyloxy)propyl]-1H-indol-2-yl)-1H-pyrazol-3-olExample 168A ethyl3-(1-(3-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indol-2-yl)-3-oxopropanoate

A solution of1-(3-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indole-2-carboxylic acid(EXAMPLE 103) (536 mg) and 1,1′-carbonyldiimidazole (200 mg) intetrahydrofuran (10 ml) was stirred at room temperature. overnight. To asuspension of potassium ethyl malonate (419 mg) in acetonitrile (10 ml)and triethylamine (0.515 ml) was added magnesium chloride (300 mg) andthe mixture was stirred at room temperature for 4 hours then cooled inan ice bath. The above-prepared solution was added dropwise to the firstsolution, and the resultant suspension was stirred at room temperaturefor three days. After this time the solvent was removed in vacuo, theresidue was taken up in toluene (50 ml), cooled (ice bath), andaqueousHCl (12%) was slowly added. The mixture was warmed to roomtemperature and extracted twice with ethyl acetate. The combined layerswere washed with aqueous NaHCO₃, and brine and dried over Na₂SO₄. Afterconcentration of the solvent, the residue was loaded on a column andeluted with 5% ethyl acetate in hexane to give the title compound.

Example 168B1-methyl-5-(4-(2-methylphenyl)-1-[3-(1-naphthyloxy)propyl]-1H-indol-2-yl)-1H-pyrazol-3-ol

To a solution of EXAMPLE 168A (75 mg) in dioxane (2 ml) and water (1 ml)was added acetic acid (0.2 ml) and hydrazine monohydrate (0.2 ml). Themixture was stirred at 100° C. overnight, and was purified via RPHPLC toafford the final product. ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (m, 1H), 7.88(m, 1H), 7.54 (m, 3H), 7.47 (d, 1H), 7.40 (d, 1H), 7.30 (m, 5H), 7.14(t, 1H), 6.88 (d, 2H), 6.23 (s, 1H), 5.70 (s, 1H), 4.91 (m, 2H), 4.21(m, 2H), 3.51 (m, 3H), 2.36 (m, 2H), 2.14 (s, 3H)

Example 1694-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-2-(1H-tetraazol-5-yl)-1H-indoleExample 169A1-(3-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indole-2-carboxamide

To a solution of143-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indole-2-carboxylic acid(EXAMPLE 103) (0.9 g) in dichloromethane containing oxalyl chloride (2mL) was added a few drops of N,N-dimethylformamide. The mixture wasstirred for 3 hours at room temperature. The mixture was concentratedunder vacuum and the residue was dissolved in dichloromethane (20 ml)and added to a cooled (0° C.) solution of concentrated ammonia in water(30 ml). After the addition, the mixture was stirred for 2 hours andthen extracted with ethyl acetate (200 ml). The organic layer was thenwashed with water, brine and dried over Na₂SO₄. Evaporation of thesolvent gave the title compound.

Example 169B1-(3-(naphthalen-1-yloxy)propyl)-4-o-tolyl-1H-indole-2-carbonitrile

To a cooled (0° C.) solution of EXAMPLE 168A (880 mg) in tetrahydrofuran(10 mL) and dichloromethane (2 ml) and triethylamine (2 ml) was added,followed by the addition of trifluoroacetic anhydride (2 ml) dropwise.After the addition, the mixture was stirred for 3 hours at 0° C. Afterthis time the mixture was diluted with ethyl acetate (200 mL) and water(80 mL). The aqueous layer was extracted with ether twice. The combinedextracts were washed with water (×3), brine and dried over Na₂SO₄.Evaporation of solvent gave crude product.

Example 169C4-(2-methylphenyl)-1-[3-(1-naphthyloxy)propyl]-2-(1H-tetraazol-5-yl)-1H-indole

To a mixture of EXAMPLE 168B (416 mg) in N,N-dimethylformamide (10 ml)was added NaN₃ (281 mg) and NH₄Cl (231 mg). The mixture was stirred atreflux overnight. After this time the mixture was concentrated undervacuum and the residue was partitioned between ethyl acetate (200 ml)and water (60 ml). The organic phase was washed with brine and driedover Na₂SO₄. After concentration of solvent, the residue was dissolvedin dimethylsulfoxide/methanol(1:1, 2 ml) and purified via RPHPLC. ¹H NMR(300 MHz, DMSO-d₆) δ 8.24 (m, 1H), 7.88 (m, 1H), 7.54 (m, 3H), 7.47 (d,1H), 7.40 (d, 1H), 7.30 (m, 5H), 7.14 (t, 1H), 6.88 (d, 2H), 6.23 (s,1H), 5.70 (s, 1H), 4.91 (m, 2H), 4.21 (m, 2H), 3.51 (m, 3H), 2.36 (m,2H), 2.14 (s, 3H).

The foregoing is meant to illustrate the invention but not to limit it.Variations and changes obvious to one skilled in the art are intended tobe within the scope of the invention as defined in the appended claims.

We claim:
 1. A compound of Formula I,

or a therapeutically acceptable salt thereof, wherein L¹ is a bond; A¹is C(O)OH; B¹ is 3-(1-naphthyloxy)propyl; C¹ is R¹; D¹, E¹ and F¹ areeach H; R¹ is phenyl which is unfused or fused with benzene; wherein R¹is unsubstituted or substituted with one or two or three or four or fivesubstituents independently selected from the group consisting of R¹⁰,OR¹⁰, OCH₂R¹⁰, SR¹⁰, S(O)R¹⁰, SO₂R¹⁰, C(O)R¹⁰, CO(O)R¹⁰, OC(O)R¹⁰,OC(O)OR¹⁰, NO₂, NH₂, NHR¹⁰, N(R¹⁰)₂, CH₂R¹⁰, C(O)NH₂, C(O)NHR¹⁰,C(O)N(R¹⁰)₂, NHC(O)R¹⁰, NR¹⁰C(O)R¹⁰, C(O)NHOH, C(O)NHOR¹⁰, C(O)NHSO₂R¹⁰,C(O)NR¹⁰SO₂R¹⁰, SO₂NH₂, SO₂NHR¹⁰, SO₂N(R¹⁰)₂, CF₃, CF₂CF₃, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR¹⁰, C(N)N(R¹⁰)₂, ═NO-(alkylene)-C(O)CF₃, CNOH,CNOCH₃, OH, (O), N₃, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and I; R¹⁰ isR¹¹, R¹², R¹³ or R¹⁴; R¹¹ is phenyl which is unfused or fused withbenzene, heteroarene or R^(11A); R^(11A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R^(12A) is heteroaryl which isunfused or fused with benzene, heteroarene or R^(12A); R^(12A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹³ iscycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, eachof which is unfused or fused with benzene, heteroarene or R^(13A);R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁴ is alkyl, alkenyl or alkynyl, each of which isunsubstituted or substituted with one, two, three, four or fivesubstituents independently selected from the group consisting of R¹⁵,OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, C(O)R¹⁵, C(O)NH₂,C(O)NHR¹⁵, C(O)N(R¹⁵)₂, NHC(O)R¹⁵, NR¹⁵C(O)R¹⁵, NHSO₂R¹⁵, NR¹⁵SO₂R¹⁵,NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, NHC(O)NH₂,NHC(O)R¹⁵NHC(O)N(R¹⁵)₂, NR¹⁵C(O)N(R¹⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃,CF₂CF₃, F, Cl, Br and I; R¹⁵ is R¹⁶, R¹⁷, R¹⁸ or R¹⁹; R¹⁶ is phenylwhich is unfused or fused with benzene, heteroarene or R^(15A); R^(15A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁷is heteroaryl which is unfused or fused with benzene, heteroarene orR^(16A); R^(16A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁸ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(18A); R^(18A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with R²⁰; R²⁰ isphenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;wherein R¹¹, R¹², R¹³, R¹⁶, R¹⁷, and R¹⁸ are independently unsubstitutedor substituted with one or two or three or four or five substituentsindependently selected from the group consisting of R²¹, OR²¹, OCH₂R²¹,SR²¹, S(O)R²¹, SO₂R²¹, C(O)R²¹, CO(O)R²¹, OC(O)R²¹, OC(O)OR²¹, NO₂, NH₂,NHR²¹, N(R²¹)₂, CH₂R²¹, C(O)NH₂, C(O)NHR²¹, C(O)N(R²¹)₂, NHC(O)R²¹,NR²¹C(O)R²¹, C(O)NHOH, C(O)NHOR²¹, C(O)NHSO₂R²¹, C(O)NR²¹SO₂R²¹,(alkylene)-C(O)CF₃, CNOH, CNOCH₃, OH, (O), N₃, CF₃, CF₂CF₃, OCF₃,OCF₂CF₃, F, Cl, Br and I; and R²¹ is alkyl, alkenyl, alkynyl, phenyl,heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl.
 2. Thecompound of claim 1, or a therapeutically acceptable salt thereof,wherein R¹ is unsubstituted or substituted with one or two or threesubstituents independently selected from the group consisting of R¹⁰,OR¹⁰, C(O)R¹⁰, NO₂, N(R¹⁰)₂, C(O)NHR¹⁰, SO₂N(R¹⁰)₂, C(O)OH, OH, (O),CF₃, OCF₃, F, Cl, Br and I; R¹⁰ is R¹¹, R¹², R¹³ or R¹⁴, R¹¹ is phenylwhich is unfused or fused with benzene, heteroarene or R^(11A); R^(11A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹²is heteroaryl which is unfused or fused with benzene, heteroarene orR^(12A); R^(12A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹³ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with benzene,heteroarene or R^(13A); R^(13A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁴ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one, two,three, four or five substituents independently selected from the groupconsisting of R¹⁵, OR¹⁵, S(O)R¹⁵, SO₂R¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, C(O)R¹⁵,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, NHC(O)R¹⁵, NR¹⁵C(O)R¹⁵, NHSO₂R¹⁵,NR¹⁵SO₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂,NHC(O)NH₂, NHC(O)R¹⁵NHC(O)N(R¹⁵)₂, NR¹⁵C(O)N(R¹⁵)₂, OH, (O), C(O)OH, CN,CF₃, OCF₃, CF₂CF₃, F, Cl, Br and I; R¹⁵ is R¹⁶, R¹⁷, R¹⁸ or R¹⁹; R¹⁶ isphenyl which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁷ is heteroaryl which is unfused or fused withbenzene, heteroarene or R^(16A); R^(16A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁸ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, each of which is unfused orfused with benzene, heteroarene or R^(81A); R^(18A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁹ is alkyl,alkenyl or alkynyl, each of which is unsubstituted or substituted withR²⁰; R²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl orheterocycloalkyl; wherein R¹¹, R¹², R¹³, R¹⁶, R¹⁷, and R¹⁸ areindependently unsubstituted or substituted with one or two or three orfour or five substituents independently selected from the groupconsisting of OR²¹, NO₂, CF₃, F, Cl, Br and I; and R²¹ is alkyl,alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl orheterocycloalkyl.
 3. The compound of claim 2, or a therapeuticallyacceptable salt thereof, wherein R¹⁰ is R¹¹, R¹², R¹³ or R¹⁴; R¹¹ isphenyl which is unfused or fused with benzene; R¹² is heteroaryl; R¹³ iscycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; R¹⁴ isalkyl, alkenyl or alkynyl, each of which is unsubstituted or substitutedwith one, two, three, four or five substituents independently selectedfrom the group consisting of R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, NH₂,NHR¹⁵, N(R¹⁵)₂, C(O)R¹⁵, C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHSO₂R¹⁵, NR¹⁵SO₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵, SO₂NH₂,SO₂NHR¹⁵, SO₂N(R¹⁵)₂, NHC(O)NH₂, NHC(O)R¹⁵NHC(O)N(R¹⁵)₂,NR¹⁵C(O)N(R¹⁵)₂, OH, (O), C(O)OH, CN, CF₃, OCF₃, CF₂CF₃, F, Cl, Br andI; R¹⁵ is R¹⁶, R¹⁷, R¹⁸ or R¹⁹; R¹⁶ is phenyl; R¹⁷ is heteroaryl; R¹⁸ iscycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; R¹⁹ isalkyl, alkenyl or alkynyl, each of which is unsubstituted or substitutedwith R²⁰; R²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl orheterocycloalkyl; wherein R¹¹, R¹², R¹³, R¹⁶, R¹⁷, and R¹⁸ areindependently unsubstituted or substituted with one or two or three orfour or five substituents independently selected from the groupconsisting of OR²¹, NO₂, CF₃, F, Cl, Br and I; and R²¹ is alkyl,alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl orheterocycloalkyl.
 4. The compound of claim 3, or a therapeuticallyacceptable salt thereof, wherein R¹⁰ is R¹¹, R¹³ or R¹⁴; R¹¹ is phenylwhich is unfused or fused with benzene; R¹³ is heterocycloalkyl; R¹⁴ isalkyl or alkenyl, each of which is unsubstituted or substituted withone, two, three, four or five substituents independently selected fromthe group consisting of R¹⁵, OR¹⁵, SO₂R¹⁵, N(R¹⁵)₂, F, Cl, Br and I; R¹⁵is R¹⁶, R¹⁸ or R¹⁹; R¹⁶ is phenyl; R¹⁸ is heterocycloalkyl; R¹⁹ isalkyl; wherein R¹¹ and R¹⁶ are independently unsubstituted orsubstituted with one or two or three or four or five substituentsindependently selected from the group consisting of OR²¹, NO₂, CF₃, F,Cl, Br and I; and R²¹ is alkyl.
 5. The compound of claim 1, ortherapeutically acceptable salt thereof, wherein the compound isselected from the group consisting of:3-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid; 3-(1-naphthyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(3-(((3-(dimethylamino)propyl)amino)carbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(1,1′-biphenyl-2-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(2-methylphenyl)-1-(3-(2-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(3-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(3-chlorophenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid; 1-(3-(1-naphthyloxy)propyl)-3-phenyl-1H-indole-2-carboxylic acid;1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid;1-(3-(1-naphthyloxy)propyl)-3-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid;1-(3-(1-naphthyloxy)propyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxylicacid;1-(3-(1-naphthyloxy)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxylicacid;3-(2,3-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(2,5-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(3,4-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(3,5-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(2,5-dimethoxyphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(3,4-dimethoxyphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;1-(3-(1-naphthyloxy)propyl)-3-(3-(piperidin-1-ylcarbonyl)phenyl)-1H-indole-2-carboxylicacid;3-(4-fluoro-3-(morpholin-4-ylcarbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid; 3-(3-(((2-methoxyethyl)aminocarbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(3-((dimethylamino)sulfonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid;3-(3-(morpholin-4-ylmethyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid; carboxylic acid;3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid; and3-(2,6-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylicacid.
 6. A composition comprising an excipient and the compound ortherapeutically acceptable salt of claim
 1. 7. A composition comprisingan excipient and the compound or therapeutically acceptable salt ofclaim
 2. 8. A composition comprising an excipient and the compound ortherapeutically acceptable salt of claim
 3. 9. A composition comprisingan excipient and the compound or therapeutically acceptable salt ofclaim
 4. 10. A composition comprising an excipient and the compound ortherapeutically acceptable salt of claim
 5. 11.1-[3-(1-Naphthyloxy)propyl]-3-[4-(trifluoromethoxy)phenyl]-1H-indole-2-carboxylicacid or a therapeutically acceptable salt thereof.
 12. A compositioncomprising an excipient and1-[3-(1-naphthyloxy)propyl]-3-[4-(trifluoromethoxy)phenyl]-1H-indole-2carboxylicacid or a therapeutically acceptable salt thereof.